Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the central nervous system (CNS) caused by an interplay between genetic and environmental factors. Epstein-Barr Virus (EBV) infection is hypothesized to be a causal risk factor for MS and is associated with a 32-fold increase in MS risk [1]. Studies have found that EBV infection in adolescence is associated with a particularly increased risk ^[2][3][2,3] suggesting that adolescence is a critical period for MS susceptibility in adult-onset MS. EBV infection is probably not sufficient to cause MS by itself. Several other environmental risk factors have shown consistent associations with increased MS risk, such as vitamin D deficiency, low sun exposure, a history of smoking, and a high body mass index ^[4][5][4,5] Exposure at a young age, especially in adolescence, seems to be critical for these risk factors ^{[6][7][8][9][10]}[6,7,8,9,10].

Psychological stress has been considered to affect MS since the initial description of the disease in the 19th century, when Jean-Martin Charcot described “long-continued grief or vexation” as being related to the onset of the disease [11]. However, stress is still a controversial risk factor for MS due to limited evidence and heterogeneous study designs in the existing literature ^[12][13][12,13] The association between stress and MS disease activity has been studied more thoroughly than the association between stress and MS susceptibility [12]. Stress has been associated with MS relapse in both prospective and case-control studies, and the risk of MS relapse is especially elevated during the first months after a stressful event [12]. 

2. Adverse Childhood Experiences Are Associated with Increased Multiple Sclerosis Risk

Both experimental and epidemiological studies have investigated the association between MS risk and early stress or ACEs, and the majority of studies were published after 2010.

2.1. Experimental Studies

An association between early-life stress and the development of MS was supported by an experimental study that triggered early-life emotional and physical trauma in mice and found increased susceptibility to experimental autoimmune encephalomyelitis (EAE) ^[14][20]. The EAE tended to be more severe and more resistant to interferon-β treatment than in the control mice. Neonatal mice were separated from their mothers and injected with saline to induce emotional and physical distress. Exposed mice had downregulated adrenergic receptors on innate immune cells, which may result in a reduced capacity to respond adequately to stress and inflammation. Another study used shipment of neonatal laboratory mice as an early-life stressor and found that exposed mice had increased risk of EAE after immunization. They also suffered more severe clinical symptoms and had less recovery than unexposed mice ^[15][22]. The researchers found higher circulating levels of stress hormones in adult EAE mice exposed to early-life stress compared to unexposed EAE mice with the same immunization. A study using Theiler’s murine encephalomyelitis virus model found that adolescent mice exposed to prolonged maternal separation in early life had higher virus antibody titers after infection that also persisted longer, compared to control mice and mice exposed to only brief maternal separation ^[16][23]. Additionally, mice exposed to neonatal stress showed inadequate release of stress hormones after viral infection. This indicates that early-life stressors can disrupt the hypothalamus-adrenal axis and the response of the innate immune to a viral infection.

2.2. Case-Control and Cross-Sectional Studies

2.3. Case-Control and Cross-Sectional Studies

An association between ACEs and MS was reported in a German case-control study of 234 people with MS ^[17][36]. The study investigated different categories of abuse and neglect and found an increased risk of having experienced sexual or emotional abuse in childhood, as well as emotional neglect, among those with MS compared to controls ^[17][36]. A case-control study from Iran with 250 MS cases found an increased risk of exposure to weekly physical abuse in childhood compared to controls, with an unadjusted odds ratio of 18.8 ^[18][34]. A Canadian case-control study among people with immune-mediated inflammatory diseases, including 232 individuals with MS, found an increased risk of childhood maltreatment among those with disease compared to healthy controls ^[19][31], with an odds ratio of 2.4 for emotional abuse. However, a case-control study from California including 1422 MS cases did not find any increased risk of reporting ACEs in telephone interviews ^[20][29]. The ACEs included parental divorce, death or illness in the core family, disruption in living situation, and childhood abuse (physical and verbal combined). A cross-sectional study from the Icelandic Stress-And-Gene-Analysis cohort of 28,000 women, including 214 women with MS, investigated 13 ACEs ^[21][30]. The authors did not find any significant associations with MS. They found elevated risk estimates for bullying, physical neglect, parental separation, and severe sexual abuse, but the confidence intervals were wide and contained the null after adjustment for confounders. Other, smaller studies (<100 MS cases) found both increased risk ^[22][33] and no increased risk ^[23][32] of self-reported abuse and neglect in childhood in people with MS.

2.3. Cohort Studies

2.4. Cohort Studies

A population-based Danish cohort study with 2,973,993 people, including 3260 individuals with MS, assessed early-life stressors recorded in national registries, such as parental divorce and the death of parents or siblings. They found that exposure to a stressful event before the age of 18 years was associated with an 11% increased risk of MS ^[24][35]. The association was mainly driven by exposure to parental divorce. Experiencing the loss of a parent or sibling did not increase the risk of MS. A cohort study with 116,671 female participants that included 262 women with MS from the Nurses’ Health Study did not find that exposure to physical or sexual abuse in childhood or adolescence increased the risk of MS ^[25][37]. The study used a mixed cohort design. Childhood abuse was mainly assessed retrospectively. The study also included a subgroup of 49 women who developed MS 1–4 years after responding to the questionnaire regarding exposure to childhood abuse. In a large Norwegian cohort study with a prospective design, the authors followed 77,997 women who answered questionnaires regarding different types of abuse ^[26][28]. A total of 300 women developed MS during a median of 7 years of followup (range 0–17 years). The hazard rate for developing MS was 31% higher for those who had experienced any type of sexual, emotional, or physical abuse before the age of 18 years. The risk of MS was highest after sexual abuse, followed by emotional abuse, and the study found a dose–response relationship between the number of abuse categories and the risk of MS ^[26][28].

2.5. Systematic Reviews

Two systematic reviews have summarized the evidence from observational studies investigating the association between ACEs and MS ^[27][28][19,21]. The systematic reviews investigated MS onset and other clinical features of MS in association with ACEs. Both reviews concluded that the evidence supports a link between childhood stress and MS risk. They also reported that people with a history of ACEs develop MS symptoms at a younger age, that they have more fatigue and exaggerated reaction to pain, and that ACE severity is associated with an increased rate of MS relapses ^[27][28][19,21].

2.4. ACEs and MS Risk: Summary of Evidence

2.6. ACEs and MS Risk: Summary of Evidence

Taken together, the current evidence supports an association between ACEs and MS susceptibility. Among the 10 included epidemiological studies on childhood stress and MS risk, six found an association with MS risk ^{[17][18][19][22][24][26]}[28,31,33,34,35,36], whereas four did not ^{[20][21][23][25]}[29,30,32,37]. Among the studies that did not find an association, two found slightly elevated risk estimates, especially for severe or repeated sexual abuse ^[21][25][30,37] but the associations were not significant. Although all the studies included ACEs, the definition and number of ACEs differed substantially. The most studied ACE was abuse, but the types and assessments of abuse varied. The cohort study from the Nurses’ Health Study investigated physical and sexual abuse, but did not include emotional abuse ^[25][37]. The largest case-control study combined physical and verbal abuse into one abuse exposure but did not include sexual abuse ^[20][29]. These two studies did not find associations between childhood abuse and MS. Interestingly, emotional and sexual abuse were the most common abuse categories associated with MS in the studies that reported associations ^[17][19][29][31,36,38]. All studies that investigated abuse used self-reported measurements of abuse through questionnaire screening tools, except for the one that used a computer-assisted telephone interview ^[20][29]. Only one study investigated early stressors assessed by national registry data ^[24][35]. Among the four studies with >100 participants that used registry data or validated abuse questionnaires, such as the Childhood Trauma Questionnaire ^[17][19][31,36] or Adverse Childhood Experiences Questionnaire ^[21][30], all except one found an increased MS risk ^[21][30]. In the studies that reported significant results, the risk varied from an 11% increase in MS risk to 18 times higher odds of MS after ACEs. Recall bias is a potential challenge when assessing negative events occurring during childhood and may contribute to inconsistencies between studies. Childhood abuse tends to be underreported rather than overreported ^[30][39]. Only two cohort studies were not influenced by recall bias. This includes the Danish cohort study based on national registry data with deaths of household members and parental separation and the Norwegian cohort study that measured self-reported childhood abuse a median of 13 years before MS diagnosis. Both studies found associations between ACEs and MS development. Evidence of an association between ACEs and MS susceptibility is supported by findings from experimental animal models of MS documenting that early-life stressors influence the susceptibility and severity of MS-like disease in exposed mice ^[14][15][16][20,22,23]. The combined evidence from experimental and epidemiological studies suggests that childhood adverse events contribute to a subsequent increased risk of MS.

3. Potential Mechanisms Underlying ACE-Related Multiple Sclerosis Risk

ACEs are associated with a type of stress often referred to as toxic stress, which comprises prolonged and excessive activation of biological stress response systems ^[31][40]. Toxic stress occurs in relation to chronic, recurrent, or severe early-life stressors, and when adequate adult support is lacking. 

3.1. Neurodevelopment and Brain Structure

The development of the nervous system is particularly vulnerable to external stimuli during periods in childhood and early adulthood ^[32][41]. Different brain regions and neuronal pathways are sensitive to childhood abuse at different ages ^[33][42], and a range of associated molecular mechanisms may alter brain structure ^[32][41]. Ultimately, such alterations may increase the risk of neurological and neuropsychiatric disorders. Early-life stress is associated with increased permeability of the blood–brain barrier (BBB) ^[34][43]. Breakage of the BBB is also central in MS pathobiology and can occur throughout the course of the disease. Leakage through the BBB occurs even before any immune cell infiltration into the CNS and before myelin damage in MS ^[35][36][37][44,45,46]. BBB dysfunction in MS is thought to be caused by external factors, such as inflammation, but evidence suggests that alterations in the BBB are also caused by independent intrinsic mechanisms ^[38][47].

3.2. Dysregulation of Stress Responses and the Immune System

Abuse and trauma can lead to chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis and inflammation ^[39][48]. Such inflammation could be a key mechanism linking ACEs to adverse adult health. Several studies have found that ACEs are associated with elevated concentrations of pro-inflammatory markers in peripheral blood that persist into adulthood ^[40][41][49,50] such as C-reactive protein, interleukin-6, and tumor necrosis factor alpha. Inflammation is a central part of MS pathobiology ^[42][51]. A dysregulated HPA axis is seen in MS ^[43][52]. High levels of the stress hormone cortisol are seen in over 50% of MS patients, and the immune cells of MS patients have higher resistance to glucocorticoids than immune cells in the controls, resulting in disrupted regulatory glucocorticoid response ^[43][52]. A dysfunctional stress system influences the immune system, and these interactions are relevant to MS pathogenesis.

3.3. The Neuroimmune Network Hypothesis

Childhood adversity not only influences individual organ systems but can also interact with the interplay between them. The neuroimmune network hypothesis claims that early-life adversity influences the crosstalk between peripheral inflammation and neural networks involved in the processes that make up the behavioral response to threat, reward, and control ^[44][53]. This disturbed crosstalk results in low-grade inflammation that contributes to a “pre-disease state”. The inflammation also affects the brain, where inflammatory cytokines alter cortico-amygdala threat circuits and cortico-basal ganglia reward circuits in a way that is believed to predispose individuals to risky health behaviors, such as smoking and high-fat diet consumption ^[44][53].

3.4. EBV

Emotional stress can reactivate herpes viruses, such as EBV ^[45][54]. Over 90% of the adult population is infected with EBV by their mid-20s. The virus appears in a latent resting state in immunocompetent individuals ^[46][55]. Early-life stress with exposure to ACEs is associated with high EBV antibody titers as an adult ^[47][48][49][56,57,58]. High EBV antibody titers are also associated with an increased MS risk ^[50][51][59,60]. EBV is believed to be a causal risk factor for MS [1], and genetic variants associated with reduced control of the EBV infection increase the MS risk ^[52][61]. It is unknown whether exposure to ACEs influences the immune response to the primary infection of EBV.

3.5. Genetics and Epigenetics

An individual’s risk of developing stress-related disorders after ACEs depends, in part, on genetic susceptibility. Epigenetic modifications have been seen in people exposed to childhood abuse, with altered expression of stress-related genes and increased risk of posttraumatic stress disorder (PTSD) in adulthood ^[53][62]. Stress disorders, such as PTSD, are associated with an increased risk of MS ^[54][55][63,64] There are well-known interactions between the main environmental risk factors for MS, such as EBV, smoking, adolescent overweight, vitamin D, and sun exposure, and the main genetic risk variant for MS; HLA-DRB*15:01 ^[56][57][58][65,66,67]. This means that the risk for MS increases substantially if exposed to both an environmental risk factor and the genetic variant HLA-DRB*15:01 than it does for each factor separately. The main mechanism by which environmental factors interact with genetic risk variants is epigenetic changes ^[59][68]. Epigenetic changes are seen in both the brain and immune cells in people with MS ^[60][69]. Studies have yet to investigate interactions between ACEs and genetic risk factors for MS, and epigenetic changes in people with MS who have been exposed to ACEs.

3.6. Shortening of Telomere Lengths

Telomeres represent protective caps at the end of all chromosomes. They shorten as the cell ages. Adults exposed to ACEs have an accelerated shortening of telomere lengths ^[61][70]. People with MS show the same accelerated telomere shortening ^[62][71]. Environmental MS risk factors, such as obesity and smoking, contribute to telomere shortening ^[63][72]. Accelerated telomere shortening is mediated by chronic inflammation and oxidative stress, which, in turn, may cause genetic instability and dysfunction of immune cells ^[63][72]. Telomere shortening may be one mechanism for ACE-induced MS risk.

3.7. Behavior and Lifestyle

ACEs are associated with a range of behavioral and lifestyle factors that are also associated with increased MS risk, such as smoking, high body mass index, adverse socioeconomic status, and physical inactivity ^{[4][64][65][66][67]}[4,25,73,74,75]. This highlights the importance of taking these well-known risk factors into account when examining the impact of ACEs on MS. Such factors may fully or partially mediate the association between ACEs and MS. Thus, it is crucial to include such variables in regression models to assess the direct effect of ACEs on MS risk.