[Draft 01]
The Thymus Modulates Emotional Regulation In Humans — How a dysregulation of emotions leads to gut issues and immune diseases and how childhood trauma impacts these diseases
Abstract
This paper proposes that the thymus modulates emotional regulation in humans, with dysregulation contributing to gut and immune disorders. The thymus functions as both an organ of the lymphatic system and the endocrine system. The thymus is involved in the maturation of T-Cells and as an endocrine gland, produces hormones like thymosin, which fuel the production of T-Cells and modulate the hypothalamic-pituitary-adrenal axis.
The thymus is most active during childhood and adolescence and gradually involutes by late adulthood. This development parallels the study where children learn to emotionally regulate themselves only after a specific age. The vagus nerve, the 10th cranial nerve, originates from the brain stem, innervates the thymus and branches to the celiac plexus. The celiac plexus is a bundle of nerves that are connected to the renal and adrenal glands, the pancreas and the duodenum, the small intestine. Thus, the celiac plexus is directly involved with the synthesis of hormones in the gut.
Here, the vagus nerve acts as a phone link between the gut, the thymus and the brain.
When the brain detects environmental stressors, it relays this information to the hypothalamus via the limbic system. The hypothalamus-pituitary axis then activates to produce cortisol and adrenaline. The vagus nerve relays signals to the celiac plexus and the thymus regarding this cortisol and adrenaline production. When a child cries and their caregivers respond with neglect, they feel that the world and the caregivers are not safe, keeping them in a constant fight-or-flight response. An excess of cortisol in the long run suppresses the production of hormones in the thymus, reducing production of T-Cells as well.
Childhood trauma disrupts this Thymus-Vagus Nerve-Celiac Plexus circuit with an overload of cortisol and adrenaline. The result is reduced thymic T-Cell development, immune diseases and gut diseases and emotional dysregulation.
Introduction
Early childhood trauma can lead to a number of psychological issues, including emotional dysregulation. Used to describe a symptom of Borderline Personality Disorder, emotional dysregulation — as defined by Dr Marsha Linehan — is the inability to effectively manage or control the intensity and duration of emotional responses. According to Dr Linehan's Biosocial Theory, emotional dysregulation stems from a transaction between biological vulnerability and an invalidating environment, where an individual's emotional experiences are persistently dismissed, criticised or punished. It states that the biology and the environment don't just work independently, but work in a feedback loop. An emotionally vulnerable child may react severely to a situation, who then faces punishment for this reaction. In response, the child faces emotions that are even more extreme, and this causes even more punishment. This feedback loop may disrupt the HPA axis by keeping the child in a fight-or-flight state.
The fight-or-flight state, also known as hyperarousal or acute stress response, is a physiological reaction to a perceived threat. This term is coined by Walter Bradford Cannon whose theory suggests how adrenaline and cortisol among many other chemicals are released into the body when in contact with said threat. For a neglected child, the fight-or-flight response never ends.
Eventually, this high cortisol and adrenaline state may come in the form of somatic symptoms like lethargy from the weakened immune system and gut issues from the disrupted vagus nerve signals to the celiac plexus due to the dysregulation of the Thymus-Vagus Nerve-Celiac Plexus Circuit. This may lead to or be comorbid with other chronic illnesses like Poly-Cystic Ovarian Syndrome, Irritable Bowel Syndrome, Cushing's Syndrome, etc. These chronic illnesses are long-lasting health issues, typically lasting a year or more, that require ongoing medical care and often limit daily activities.
With growing research on the impact of psychological trauma on gut issues and immune diseases paralleling documented cases, this paper seeks to identify the core causes of these issues using a neuro-psycho-physiological perspective.
The purpose of this paper is to review how emotional dysregulation happens in an individual and how that affects the overall health of an individual.
Stress
Models of stress have evolved from acute to chronic, appraised transactions, yet none trace glucocorticoid effects to their thymic targets. This section critiques existing frameworks and positions thymic involution as the missing biological link between childhood trauma and emotional dysregulation.
Walter Bradford Cannon in his 1915 seminal book, Bodily Changes in Pain, Hunger, Fear and Rage, discovered that when an individual encounters a terrifying or stressful event, the brain activates the sympathetic nervous system and stimulates the adrenal medulla to release a rush of stress hormones, primarily adrenaline and noradrenaline. This describes an acute event that an organism goes through. For example, when a child is neglected by its caregivers.
To find out what an ongoing stressful situation can do to the body, we can see how endocrinologist Hans Selye's study on rats affected them. He defined stress as the body's nonspecific physiological response to any demand. He found that there is a universal physiological reaction that is caused by diverse stressors, which he named General Adaptation Syndrome, or simply, GAS. The three stages of GAS are as follows — 1) Alarm Reaction: initial fight-or-flight, the sympathetic nervous system activates and the adrenal glands release hormones like adrenaline and noradrenaline, consistent with Cannon's theory of fight-or-flight; 2) Stage of Resistance: the body adapts by maintaining elevated levels of stress hormones and blood pressure. While the body functions at a higher level of adaptation, prolonged stress during this phase can disrupt the immune and digestive systems, leading to symptoms like irritability, stomach problems, and difficulty concentrating, ; 3) Exhaustion Stage: chronic stress eventually depletes the body’s physical and mental resources, causing the ability to cope to diminish significantly. This stage is characterized by fatigue, burnout, and decreased stress tolerance, and it increases the risk of serious health conditions such as heart disease, hypertension, diabetes, and mental health disorders like depression or anxiety. Selye discovers the “Stress Triad” — the thymus shrinks, the small intestine bleeds and the adrenal glands enlarge — in line with Cannon's fight-or-flight system of stress, wherein the body produces excess adrenaline through the adrenal glands, enlarging them in the process.
Then, in 1966, psychologist Richard Lazarus published Psychological Stress and the Coping Process, introducing the Cognitive Appraisal Theory of Stress. This model suggests stress is not just an automatic response to a threat, but a subjective transaction between an individual and their environment. When a child perceives neglect as a threat and that neglect is ongoing, the child is stuck in the second stage of Selye's stress model, a constant mode of HPA activation and eventually as it grows up, falls into the third stage of Selye's stress model, which is exhaustion and chronic illness.
In 2011, neuroscientist Stephen W. Porges wrote about the Polyvagal Theory. The theory maps how the vagus nerve regulates bodily states in response to stress, trauma, and social cues through three evolutionary pathways— 1)Ventral Vagal Pathway: The newest evolutionary system. It supports the "social engagement system," promoting feelings of safety, calm, and connection. 2) Sympathetic Nervous System: The fight-or-flight response. It mobilizes the body to react when the ventral vagal system perceives threat. 3) Dorsal Vagal Pathway: The most primitive system. It triggers the "freeze" or collapse/shutdown response when a threat is overwhelming. The dorsal vagal pathway shows how chronic stress can shut down the body's systems, as is also mentioned by Selye's work. When a child perceives caregiver neglect as life threatening, their body can shut down.
This model of stress-response only covers the vagus nerve and does not mention the thymus. Many theories talking about stress and their response, cover the adrenal glands and the vagus nerve — and in turn, the celiac plexus — for regulating and modulating the response but only Selye notes thymus involution as a consequence of stress. What the polyvagal theory misses is the influence of the thymus on regulation of emotions.
The Thymus
The thymus has been historically classified as a primary lymphoid organ responsible for the maturation of T-Cells. However, its endocrine function — producing thymulin, thymosin, thymopoietin, hormones that regulate both T-Cell maturation and hypothalamic-pituitary activities puts it in the category of both a lymphatic and endocrine organ [Bodey et al, 2000]. It has dense innervations from the vagus nerve, and documented sensitivity to glucocorticoids, yet it still is absent from current models of trauma-related gut and autoimmune disease. This section establishes the thymus as the missing neuroendocrine link between childhood trauma and physiological issues.
Located right above the heart and behind the breastbone, the anterior mediastinum, the thymus provides the microenvironment for T-cell receptor gene rearrangement and positive/negative selection. As an endocrine organ, it produces thymosin to stimulate T-cell differentiation and thymopoietin to modulate pituitary hormone release [Bodey et al. 2000]. Crucially, thymic function is not isolated: pituitary growth hormone and pineal melatonin regulate thymulin production, while thymic peptides feedback to classical endocrine glands [Bodey et al. 2000]. This bidirectional neuroendocrine communication positions the thymus within the HPA axis circuitry implicated in trauma responses [Kuhlman et al. 2017].
In 1936, Hans Selye published a paper where he formulated the General Adaptation Syndrome (GAS). Doing this experiment also led to the discovery of Selye's “Stress Triad”, a set of physical changes universally found in his stressed subjects — Adrenal Gland Enlargement, Shrinkage of the Thymus and Lymph Nodes, and Bleeding Stomach (Duodenal Ulcers). This mechanism is glucocorticoid-driven. High levels of stress release glucocorticoids (like cortisol) into the bloodstream. Cortisol targets immature cortical T-Cells (thymocytes), inducing rapid apoptosis (programmed cell death) and acute involution (rapid shrinking) of the thymus [G.G. Steinmann et al, 1985]. This is to say that chronic stress biochemically dismantles the organ responsible for immune self-tolerance.
Thymic deterioration is a continuous process beginning in the first year of life, which is heavily influenced by stress and cortisol rather than strictly by puberty [G.G. Steinmann et al, 1985]. Research by Steinmann demonstrated that the greatest volume and functional capacity of the human thymus occur in the first year of life. After this, the functional epithelial space undergoes continuous, progressive shrinkage by about 3% per year. This places the maximal thymic activity — and maximal glucocorticoid vulnerability — in infancy and early childhood. This overlaps with the sensitive period for emotional regulation development, during which children transition from caregiver-dependant co-regulation to self regulation between ages 2-5 [Silkenbeumer et al, 2018]. fMRI neuroimaging shows that this behavioural shift is underpinned by increased connectivity between amygdala and dorsal anterior cingulate cortex in older children [Perlman and Pelphrey 2010], reflecting maturation of top-down control circuits.
Thus, three developmental systems converge in early childhood: 1) thymic mass and thymosin output [Steinmann et al, 1985], 2) emotional regulation circuitry [Perlman and Pelphrey 2010; Silkenbeumer et al, 2018] and 3) HPA axis calibration [Kuhlman et al. 2017]. All three are glucocorticoid-sensitive. When childhood adversity produces chronic HPA activation, as outlined in Kuhlman's psychoneuroimmune model, the resulting cortisol exposure may simultaneously accelerate thymic involution [Selye 1936] and disrupt the establishment of emotional regulation [Silkenbeumer et al, 2018]. This positions the thymus as a biological substrate for Linehan's “biological vulnerability” — an organ whose stress induced degradation could explain both immune and emotional dysregulation post trauma.
Despite this convergence, no current model of emotional dysregulation or trauma related disease integrates thymic endocrine function. The following sections examine vagal innervation of the thymus to build the case for a thymus-vagus-celiac circuit.
The Vagus Nerve and The Celiac Plexus
The 10th Cranial Nerves (CNX), also known as the Vagus Nerve or Vagal Nerves, are the main nerves of the parasympathetic nervous system. This system controls specific body functions such as digestion, heart rate and immune system.
The vagus nerves are the longest cranial nerve, running from the brainstem (medulla oblongata) to the large intestine.
The celiac plexus is a network of nerves in your abdomen behind the stomach and in front of the diaphragm. The celiac plexus gets parasympathetic fibres from the vagus nerve. The celiac plexus connects to the small intestine and the adrenal glands also. Hence we see that the celiac plexus sends info to and from the adrenal glands, the small intestine and the vagus nerve. When Selye discovered the Stress Triad, we see this happening in the form of stomach ulcers caused by chronic stress.
Neurons located within specific brainstem nuclei directly project nerve fibers to the thymus. In neuroanatomy, these specific brainstem areas are well-established hubs for parasympathetic outflow. [Bulloch and Moore, 1981] Another group of researchers successfully identified noradrenergic (sympathetic) fibers alongside parasympathetic fibers localized within the thymic cortex, medulla, and around its blood vessels. [David L Felten et al, 1985] To definitively clarify that these fibers were parasympathetic and didn't just belong to local cells, researchers published dedicated histochemical and immunocytochemical studies using antibodies against the chemical that stamps the fibres as true parasympathetic nerves. [U. Singh et al, 1986] To identify parasympathetic nerve fibres, Bulloch used techniques to specifically stain enzymes that create and break down acetylcholine, a hallmark neurotransmitter of parasympathetic fibers, but because some local, non-neuronal thymic cells can also express acetylcholine, chemical staining alone was not always enough to prove a central nervous system connection. So they used a technique called retrograde tracing, where they injected the thymus of mice with an enzyme and traced it back to a section of the parasympathetic nervous system, the nucleus ambiguus and the retrofacial nucleus in the brainstem. The vagus nerve is known to originate from these parts in the brainstem, so this establishes the connection between the vagus nerve and the thymus.
To double-check their findings, they used a neurotoxin that selectively destroys sympathetic nerve terminals while leaving parasympathetic fibers completely intact.
The vagus nerve is cited as the fight-or-flight hub in Porges’ polyvagal theory, and though these connections from the vagus nerve to the thymus are known, the thymus is still left out of the equation of childhood trauma models.
The Thymus-Vagal-Celiac Circuit
Stress is detected by the brain and sends signals to the hypothalamus to produce a hormone CRH. This CRH is produced and stimulates the pituitary gland to produce another hormone ACTH. ACTH sends signals to the adrenal glands to produce cortisol and adrenaline. The hormones travel through blood but the signals to send them remain in the nervous system. Meanwhile, sympathetic nerve fibres fire the celiac plexus to activate the adrenal glands and the duodenum (the small intestine). This is why Selye's stress triad mentions adrenal enlargement as well as duodenal ulcers, the small intestine also gets signals via the celiac plexus.
The vagus nerve also sends signals to the thymus, which upon receiving cortisol from the bloodstream, shrinks in size minutely, this is also explained by Selye's stress triad as well as G.G. Steinmann. Without thymulin, the vagus nerves send more signals between the HPA axis and the thymus, and this makes the new gut-brain axis. The gut-brain axis classically refers to the HPA-vagus nerve-stomach connection(celiac plexus) but does not mention the thymus. The vagus nerve acts as a communication link between the endocrine system and the lymphatic system, with the thymus at its forefront. The thymus regulates anti-inflammatory peptide hormones like thymulin which may soothe the nervous system or calm a person down, by modulating the HPA axis.
Under normal circumstances, this circuit switches off and the thymus releases these hormones upon the stressor leaving. However, in cases like a neglected child, this switch is broken and never shuts off, causing three things: 1) the thymus to shrink abnormally (Selye) and thus causing immune dysfunction (Steinmann), 2) the celiac plexus to stay activated, leading to gut issues and adrenal gland dysfunction (Selye), 3) the HPA axis stays fully activated as in Linehan's biosocial model
Implications and Limitations
Linehan's biological vulnerability is a shrunken thymus that cannot produce thymulin to shut off CRH hormone. This same broken circuit can explain why BPD is comorbid with IBS [Niesten, Isabella J M et al., 2014], autoimmune disease [Forte, A R C C et al., 2023] and PCOS [Stefan Roepke et al., 2010]. IBS can be caused by a “stuck” celiac plexus, autoimmune disease can be caused by thymic loss which means no immune self-tolerance, and PCOS can be caused by chronic cortisol and HPA activation.
This could be the reason for why Dialectical Behavioural Therapy (DBT) has high relapse rates for emotional dysregulation. DBT cannot regrow the thymus. SSRIs help with HPA activation but ignore the thymus and its hormones entirely.
The limitations are that this is purely a hypothetical model. Direct thymulin and thymus studies are not undertaken due to the location of the organ. Steinmann's observations were postmortem and no other study undertakes Steinmann's observations, Selye's observations and Linehan's biosocial theory into account. This is a broad category of study.
If correct, adults with childhood trauma should show: 1) smaller thymic mass, 2) blunted cortisol awakening (CAR) and 3) lower thymic hormone levels. This can be treated through early intervention to conserve thymic mass, thymulin analogues for medicine and vagal nerve stimulating therapies.
Conclusion
This paper proposes the thymus as the missing puzzle link for neuroendocrine and immune disorders comorbid with psychological issues. Selye and Steinmann discovered that the thymus shrinks due to a high stress environment. Most trauma theories treat it as if it doesn't exist, this theory treats it as the main framework for emotional dysregulation as described by Dr Marsha Linehan. The development of the thymus overlaps with the development of children's emotional regulation skills — when they learn to regulate themselves, between ages 4-5. This evidence is also shown through fMRI imaging in older kids learning to regulate themselves — it shows a pattern of innate regulation. When this window of ages 0-5 is riddled with a high stress environment, their thymic capacity greatly reduces. The result is a weakened immune system, a disrupted HPA axis and a celiac plexus stuck in fight-or-flight. This has implications for comorbidities in psychological issues with chronic illness. People with childhood trauma would show reduced thymic mass, etc. The limitations are that it's a purely hypothetical model with no primary data to back it up.
