Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS; Naranch et al., 2002) and Gulf War Illness (GWI; Surian and Baraniuk, 2020) are characterized by fatigue, postexertional malaise (PEM), sleep disruption, neurocognitive disruption, widespread pain, orthostatic intolerance, and a wide range of interoceptive or “inner body” complaints, such as sensitivity to irritants, dyspnea, and gastrointestinal distress. We propose that heightened awareness of pain and interoceptive sensations is due to lapses in midbrain and brainstem antinociceptive and antiinteroceptive systems that ordinarily filter and suppress the transmission of these sensations to centers of conscious perception in the cerebrum. Dysfunction of midbrain, brainstem, and descending antinociceptive pathways is termed central sensitization and leads to central or neuroplastic pain.

We propose that dysfunction of midbrain and brainstem mechanisms and descending antiinteroceptive and antinociceptive pathways contribute to the pathologies of ME/CFS and GWI (Baraniuk, 2022). Dysfunctional descending inhibitory processes lead to tenderness that can be quantified by pressure-induced pain thresholds (kg) measured by dolorimetry (algometry) and tender point counts. These measures are predicted to correlate with generalized pain sensations. With regard to interoceptive discomfort, we predict that identical or separate analogous interoplastic mechanisms will contribute to interoceptive discomfort. If nociplastic and interoplastic outcomes have shared mechanisms, then pain and pressure thresholds should correlate with interoceptive complaints. ME/CFS and GWI are disabling conditions, and so measures of quality of life are anticipated to correlate with pain and tenderness. Fatigue is a difficult sensation or emotion to define, but insights may be gained by contrasting its severity with tenderness, interoception, nociception, and disability. Fatigue without other symptoms was examined by studying chronic idiopathic fatigue (CIF) subjects.

Tenderness is an objective measure of nociception that is demonstrated by applying a stimulus such as pressure to the skin in order to elicit a painful response. Tenderness has been demonstrated in ME/CFS (Naranch et al., 2002) and GWI (Surian and Baraniuk, 2020) and is a pillar of the concept of fibrositis (Bennett, 1981), central sensitization syndrome (Cuesta-Vargas et al., 2018), and the diagnosis of fibromyalgia (FM) using the 1990 criteria (Wolfe et al., 2010; Clauw, 2024). Tenderness is proposed to be the consequence of disrupted central “nociplastic” regulation of pain signaling (Nijs et al., 2021). Unmyelinated nociceptive and multimodal afferent nerves synapse with secondary interneurons in the spinal dorsal horn that ascend in the spinal cord to the brain. Pain transmission is regulated by descending antinociceptive pathways that originate in the periaqueductal gray matter and medulla and project to the dorsal horn. Interruption of the pathway(s) leads to increased perception of pain and mechanically induced tenderness. The central mechanism has been classified as nociplastic to distinguish it from nociceptive pain caused by peripheral inflammation with excessive stimulation of nerve endings and nocipathic pain resulting from injury to conducting nerves or ganglia. The absence of the descending inhibitory tone permits increased conduction of painful sensations so that a low level of peripheral stimulation that would ordinarily be insufficient to trigger signal transmission can now convey ascending perceptions of pain via spinothalamic routes. This is termed systemic hyperalgesia. In addition, dysregulation in the dorsal horn allows innocuous peripheral stimuli such as light touch, proprioception, or vibration to incorrectly generate nociceptive signals (allodynia; Jensen and Finnerup, 2014). Collectively, these processes are called central sensitization. The peripheral triggering of pain sensations, i.e., tenderness, can be measured by dolorimetry (algometry), where a pressure gauge is pressed against the skin and the pressure causing pain is recorded (kg). The nociceptive and interoceptive pathways are distinct from the highly myelinated peripheral somatosensory, proprioceptive, dermatomal, muscular, and exertioceptive nerves that synapse in the dorsal horn and ascend to the thalamus and thence through the internal capsule to the primary somatosensory cortex.

The relevance of nociplastic and presumed interoplastic mechanisms can be appreciated by examining the many symptoms that are attributed to internal organs and mucosal surfaces in ME/CFS, GWI, and FM. The evolution of diagnostic criteria for ME/CFS, GWI, FM, and CIF provides the context for quantifying the relationships between these core dimensions of disease severity and mechanisms of disease.

ME/CFS is defined by prolonged debilitating fatigue, postexertional malaise (PEM), cognitive and other physical symptoms, plus the exclusion of known chronic medical and psychiatric diseases (Fukuda et al., 1994; Carruthers et al., 2003). Prevalence is 0.1–2%, with a wide range in part because of differences in diagnostic criteria in different studies (Lim et al., 2020). The etiology has been presumed to be a post-infectious disorder (Holmes, 1988), as inferred from polio, enterovirus (Dowsett et al., 1990), Epstein–Barr (Pedersen et al., 2019), and other infectious diseases (Bannister, 1988) that may occur in sporadic or epidemic fashion, and as suggested for post-COVID-19 (coronavirus disease 2019) fatigue (Carfı̀ et al., 2020; Thaweethai et al., 2023; Fineberg et al., 2024). Evidence of autoimmunity (Sotzny et al., 2018), as well as immune, metabolome (Tomas and Newton, 2018), and autonomic (Nelson et al., 2019) dysfunction, makes the spectrum of molecular mechanism(s) more complex. Because no biomarkers have been validated, the diagnosis relies on patient history, physical examination, and the exclusion of chronic medical and psychiatric conditions based on clinical practice and routine blood work.

The diagnostic criteria for ME/CFS have evolved from lists of symptoms experienced in patient cohorts to more focused consensus approaches (Figure 1; Jason et al., 2016, 2015, 2012). Benign myalgic encephalomyelitis was introduced by Ramsay in 1973 (Ramsay, 1973) and post-infectious chronic fatigue by Holmes in 1988 (Holmes, 1988). The 1994 Centers for Disease Control and Prevention (CDC) criteria (“Fukuda”; Fukuda et al., 1994) expanded criteria by requiring more than 6 months of disabling, prolonged, or relapsing fatigue with at least four of eight ancillary symptoms: post-exertional malaise, cognitive problems with memory or concentration, unrefreshing sleep, muscle pain, joint pain, headaches, sore throat, and tender lymph nodes. Specificity is improved by requiring moderate or severe symptoms for case designation, as in the ME/CFS severity questionnaire (CFSQ) used here (Baraniuk et al., 2013a). More recent criteria have increased the emphasis on postexertional symptom exacerbations or postexertional malaise (PEM) in the 2003 Carruthers Canadian Consensus Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS; CCC; Carruthers et al., 2003; Carruthers, 2007), the 2011 Myalgic Encephalomyelitis International Consensus Criteria (International; Carruthers et al., 2011) and Systemic Exertion Intolerance Disease (SEID) defined by the Institute of Medicine in 2015 (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, and Institute of Medicine, 2015). Symptom severity should be moderate or severe and present at least half of the time (Jason et al., 2013; Sunnquist et al., 2019; Bedree et al., 2019). In 2024, the National Academy of Sciences, Engineering, and Medicine recommended considering ME/CFS and Long COVID as post-infectious diseases with potentially shared pathophysiologies (Fineberg et al., 2024). PEM refers to debilitating symptom exacerbation that impairs activities of daily living following mild physical, cognitive, or emotional stressors. Onset is often delayed 24 h, and dysfunction may last for 72 h or more (Chu et al., 2018; Stussman et al., 2020). Sleep is not refreshing, which distinguishes PEM from the temporary exertional tiredness experienced by healthy people and those with chronic illnesses who return to normal after rest and refreshing sleep. Note that postexertional malaise was not required for the 1994 Fukuda criteria (Fukuda et al., 1994), but both postexertional malaise and fatigue are required by the CCC (Carruthers et al., 2003; Carruthers, 2007), International (Carruthers et al., 2011), and SEID (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, and Institute of Medicine, 2015) criteria. Also, the SEID criteria removed pain as a requirement in order to avoid overlap with chronic nociceptive illnesses such as fibromyalgia. The shifting criteria emphasize the need to reframe the role of pain in ME/CFS and to understand patients who have chronic fatigue, pain, and interoceptive discomfort.

Fibromyalgia (FM) is the prototypical nociplastic disease with pain and tenderness due to central sensitization and systemic hyperalgesia (Nijs et al., 2021; Fitzcharles et al., 2021; Kaplan et al., 2024). Clinical criteria have evolved over the years (Clauw, 2024). The 1990 American College of Rheumatology criteria for FM required widespread pain plus tenderness to thumb pressure at ≥11 of 18 traditional tender points (Wolfe et al., 2010; Figure 1). Pressure should be sufficient to blanch the thumbnail bed or ~4 kg (Bennett, 1981). However, tender point counts correlate with catastrophizing, general distress, fatigue, depression, sleep, and orthostasis, and may be independent of pain (Giesecke et al., 2003; Petzke et al., 2003; Geisser et al., 2007; Croft et al., 1994; Geisser et al., 2003; Davydov et al., 2024). The technique is challenging to calibrate and standardize between investigators. Tenderness in FM is present diffusely throughout the body and is not localized to the 18 traditionally specified sites (Petzke et al., 2001). Therefore, tender point counts were removed from the 2010 revision of the FM criteria (Wolfe et al., 2011), even though the concept of tenderness is still considered important for FM diagnosis in clinical practice (Bettini and Moore, 2016). The 2010 revision tabulates painful body regions (Pain and Tenderness in the Past Week; Wolfe et al., 2011) and was expanded to include graded assessments of the severity of fatigue, cognitive difficulties, problems upon waking up, and somatic complaints (Figure 1; Gracely and Schweinhardt, 2015; Yunus, 2008). A modification in 2011 maintained widespread pain, fatigue, cognition, and sleep, but changed somatic complaints to nominal confirmation of headache, lower abdominal pain, and feeling depressed (Wolfe et al., 2011). The 2016 amendment excluded chronic regional pain syndrome (Wolfe et al., 2016). The criteria for fibromyalgia were reduced in 2019 to chronic widespread pain with either fatigue or sleep disturbances lasting more than 3 months (Arnold et al., 2019). Widespread sensory sensitivity is appreciated (Rafferty and Ward, 2024). These modifications increased the overlap between the criteria for FM, ME/CFS, and GWI, and blurred distinctions between these clinical entities (Ramírez-Morales et al., 2022).

Gulf War Illness (GWI) criteria overlap with ME/CFS (Figure 1). GWI was defined by meeting both the 1998 Centers for Disease Control Chronic Multisymptom Illness (CMI; Fukuda et al., 1998) and the 2000 Kansas (Steele, 2000) criteria. CMI requires two of three complaints: fatigue, mood and cognition, or musculoskeletal pain (Fukuda et al., 1998). The CMI criteria follow a tridimensional approach that probes tiredness as a psychosocial dimension, with restrained social activity due to fatigue or mood impairment, cognitive complaints with a decreased ability to maintain attention and memory impairment, and somatic musculoskeletal pain (Brurberg et al., 2014; Onozuka and Yen, 2008). A limitation is that the original criteria did not have to be graded for severity.

The Kansas criteria were defined from a population study of Kansas veterans that identified 28 symptoms organized into six domains, which were significantly more prevalent in deployed compared to non-deployed veterans of the 1990–1991 Persian Gulf War (Steele, 2000). GWI is diagnosed by having at least three of six domains with moderate or severe complaints. Although there is extensive overlap of ME/CFS and GWI symptoms, these are different diseases because ME/CFS has a sporadic onset and affects predominantly women, while GWI occurs in 25–32% of the cohort of predominantly young adult male military personnel deployed to the Persian Gulf theater of operations in 1990–1991 who were exposed to nerve agents (Sarin), pyridostigmine bromide pills, cholinesterase inhibitors, pesticides, oil well fire smoke, and other potentially pathological neurotoxic conditions (White et al., 2016; Maule et al., 2018). One quarter to one third of Gulf War veterans have developed chronically unremitting disease. GWI and ME/CFS differ in cognitive responses to exercise, with different patterns of change in functional connectivity involving dorsal midbrain and cortical regions during a difficult cognitive working memory task (Baraniuk et al., 2022; Provenzano et al., 2020). Note that pain, persistent fatigue, and postexertional malaise are not absolutely required for GWI diagnosis.

Chronic idiopathic fatigue (CIF) has been defined by significant unremitting fatigue lasting longer than 6 months (Vincent et al., 2012; Palacios et al., 2023). CIF and ME/CFS are different because the absence of significant ancillary nociceptive and interoceptive symptoms precludes the diagnosis of ME/CFS (Fukuda et al., 1994). Incidence and prevalence are comparable to ME/CFS (Van Amberg, 1990; Steele et al., 1998; Reeves et al., 2007). Almost half have comorbid insomnia, somatic disorders, anxiety, or depression (Vincent et al., 2012; Van Amberg, 1990; Reeves et al., 2007; Son, 2019). Subjects with CIF would meet the inappropriately lenient Oxford criteria and may have been included in the ill-conceived PACE study (Baraniuk, 2017). One hypothesis is that CIF represents an early expression of ME/CFS. However, CIF does not show cardiac or respiratory deterioration on 2-day maximal cardiopulmonary exercise testing in females (van Campen and Visser, 2021a,b) or males (van Campen and Visser, 2021a). CIF must be distinguished from frailty and fatigue that develop with advancing age (Wawrzyniak et al., 2016; Alexander et al., 2010). The CFSQ measurements and the rationale of the Fukuda criteria (Fukuda et al., 1994) were utilized to define a CIF subgroup that had significant fatigue but ≤ 3 other ancillary criteria (“quadrant analysis”; Baraniuk et al., 2013a; Baraniuk, 2017). The current data set provided insights into tenderness, fatigue, interoceptive, and affective elements of CIF.

For this study, dolorimetry pressure thresholds were compared between control, ME/CFS, and GWI groups. In secondary analysis, CIF subjects were selected from the pool and compared to the residual control, ME/CFS, and GWI groups. Pressure thresholds have a sexual dimorphism, so female and male subjects were examined separately for correlations with pain, interoception, fatigue, quality of life, and other measures. In contrast, symptoms were comparable across genders, and so the subjective correlations were recalculated for the entire cohort. Significant correlations were stratified to infer possible effects of nociplastic and interoplastic mechanisms.

A long-term prospective plan was put in place to collect standardized data to compare between disease groups. Data were collated from a series of protocols that were approved by the Georgetown University Institutional Review Board and Department of Defense Congressionally Directed Medical Research Program (CDMRP) Human Research Program Office (HRPO; A-15547 and A-18479) in accordance with the Declaration of Helsinki and listed in http://clinicaltrials.gov (NCT01291758 and NCT00810225). Subjects gave virtual informed consent to complete online questionnaires, followed by written informed consent for in-person evaluations to confirm their diagnoses.

GWI, ME/CFS, and healthy sedentary control (SC) subjects were recruited through personal contact, posters, and online advertisements and gave verbal informed consent to complete a battery of questionnaires (Baraniuk et al., 2013b). Paper versions were hand-entered in duplicate into Excel. All data were inspected for errors or missing data. Subjects provided in-person written informed consent for history and physical examinations to assess the Fukuda criteria (Fukuda et al., 1994; Figure 2) and Carruthers Canadian Consensus Criteria for ME/CFS (CCC; Carruthers et al., 2003; Carruthers, 2007; Figure 3), International Myalgic Encephalomyelitis (Carruthers et al., 2011), Systemic Exertion Intolerance Disease (SEID; Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, and Institute of Medicine, 2015), Chronic Multisymptom Illness (CMI; Fukuda et al., 1998; Figure 4), and Kansas (Steele, 2000; Figure 5) criteria, as well as confirmation of sedentary lifestyles (< 40 min of aerobic activity per week). Subjects were excluded because of serious chronic medical or psychiatric conditions such as psychosis (Gifford et al., 2021; Reeves et al., 2003; Jones et al., 2009; Nater et al., 2009). A history of posttraumatic stress disorder (PTSD) or depression was not an exclusion unless the subject had been hospitalized in the previous 5 years.

ME/CFS was defined by Carruthers' Canadian Consensus Criteria (CCC; Carruthers et al., 2003; Carruthers, 2007; Figure 3). The CCC requires the presence of chronic fatigue, disability, sleep disturbances, cognitive issues, PEM, and a range of diverse interoceptive complaints. GWI was defined by military service and by meeting both the CMI (Fukuda et al., 1998; Figure 4) and Kansas (Steele, 2000) criteria (Figure 5). The Kansas and CCC criteria incorporate a broad spectrum of interoceptive symptoms in contrast to the limited scope of the SEID and CMI criteria.

CMI requires two of three sets of complaints: fatigue, musculoskeletal pain, and cognitive/mood complaints. Symptoms are scored as present or absent, which leads to low specificity in the general population. To improve specificity, we required moderate or severe severity for CMI and the other criteria in our studies.

The Kansas criteria require symptoms in at least three of six domains (Figure 5). Note that it is possible to meet CMI and Kansas criteria without having fatigue.

Sedentary controls included civilians and healthy veterans who did not meet the CCC, Kansas, or CMI diagnostic criteria.

Fibromyalgia was evaluated by widespread pain, tender point counts, and the 1990, 2010, 2011, and 2016 criteria, as well as dolorimetry (Wolfe et al., 2010, 2011, 2016).

The questionnaires and physical exam allowed parallel analysis of central sensitization and nociplastic changes by dolorimetry; the number of tender points by thumb pressure at the traditional 18 tender points (Bennett, 1981); nociceptive complaints by widespread pain above and below the waist, in the axial skeleton, and on the left and right (Wolfe et al., 2010); the number of painful regions from the 2010 FM criteria (Wolfe et al., 2011); pain symptoms; fatigue; interoceptive complaints; and quality of life.

Our objective was to determine if the physical sign of tenderness, a biomarker of central hypersensitivity, was correlated with demographics, fatigue, disability, interoceptive, nociceptive, or affective symptom profiles based on self-report questionnaire results. Subjects were classified by two algorithms to first compare SC vs. ME/CFS vs. GWI, then by quadrant analysis (Figure 2) to select CIF and compare SC, CIF, ME/CFS, and GWI. The latter provided insights into the characteristics of the CIF subgroup. Differences were determined by ANOVA. Thresholds for differentiating between control, CIF, ME/CFS, and GWI were determined by receiver operating characteristics (ROC). Spearman correlations assessed relationships between variables. Women were more tender than men, so correlations and PCA that included dolorimetry outcomes were investigated separately for each gender. Questionnaire responses were equivalent between men and women and were also pooled to find relationships between subjective complaints.

Our hypothesis was that central sensitization and tenderness would correlate with fatigue, interoception, pain, and disability. The proxy for tenderness was dolorimetry pressure thresholds (kg), with Chalder for fatigue, McGill Total Score for pain, CMSI (no pain) for interoception, and the average of the SF36 Role Physical, Vitality, and Social Functioning domains for disability. Dolorimetry correlated well with the McGill Total Pain (explained variance R² = 0.30–0.40) in women (Table 3) and men (Table 4) but had weaker correlations with interoception (CMSI no pain, R² = 0.17–0.33) and poor correlations with Chalder Fatigue and disability domains (R² = 0.05–0.16, not significant). The best match was between pain and interoception (R² = 0.55–0.64), suggesting parallel increased messaging due to dampened antinociceptive and antiinteroceptive sensory inhibition. Fatigue and disability had the next best correlations (R² = 0.41–0.47). Other correlations of fatigue, disability, pain, and interoception were higher in males (R² = 0.34–0.46) than in females (R² = 0.20–0.30).

The correlation of pain and interoception suggested increased sensory perceptions of warning signals that could be due to increased afferent traffic from the periphery (e.g. nociceptive pain) or a reduction in central antinociceptive (nociplastic pain) and antiinteroceptive mechanisms with a loss of their inhibitory activities. Tenderness (dolorimetry) was more highly correlated with pain than with interoception, suggesting that nociplastic mechanism(s) of central sensitization explained more of the variance of pain than interoception processes. This would be consistent with several independent pathways contributing to each mechanism. One explanation is the anatomical difference between dorsal horn and spinothalamic pain pathways vs. cranial nerve (vagal) interoceptive pathways.

Central sensitization was poorly correlated with fatigue and disability, suggesting that the midbrain and brainstem regulatory mechanisms had little impact or that fatigue and disability were derived from higher subcortical or cortical regions. These ideas suggest a dichotomy between midbrain and brainstem inhibitory antinociceptive and antiinteroceptive pathways, as opposed to subcortical and cortical systems that evaluate these sensations in the context of homeostasis, fatigue, effort valuation, affective, emotional, and limbic dysfunction. These hypotheses can now be tested and powered using the current outcomes for future investigations of causation in ME/CFS and GWI.

Dolorimetry findings were significantly different between groups by parametric analysis (Figure 10). The data were widely skewed, and so the non-parametric ROC did not provide strong support for any specific level of dolorimetry or tender point counts to diagnose ME/CFS or GWI in males or females. However, the outcomes do support the general concept of widespread tenderness in these diseases when CIF subjects are accounted for. This was most clear for males, where thresholds were stratified as SC>CIF>ME/CFS=GWI (Figure 11). CIF subjects contributed to the left-skewed distribution for dolorimetry in the SC males. SC females had two modes for tenderness even after removing the CIF subset (Figures 2, 10). This finding may be an artifact but should be investigated in larger groups.

A surprising finding was the correlation between systemic hyperalgesia and symptoms of irritable bowel syndrome in men (R = −0.538; Table 4). This was likely due to the large number of male GWI subjects and their gastrointestinal problems but suggested that nociplastic and interoplastic mechanisms may contribute to the perception of systemic and gastrointestinal distress as a complication of gut dysbiosis (König et al., 2021; Guo et al., 2023; Nagy-Szakal et al., 2017; Malhotra et al., 2023; Nono Djotsa et al., 2024).

Despite its limitations, dolorimetry was a reliable tool to quantify changes in systemic hyperalgesia in clinical trials of a low glutamate diet in GWI (Holton et al., 2020) and fibromyalgia (Holton et al., 2012). Alternative methods to measure mechanical and other modes of hyperalgesia may be developed for diagnostic purposes and as tools with measurable outcomes in clinical research (van Driel et al., 2024; Garfinkel et al., 2022).

Chronic idiopathic fatigue (CIF; Vincent et al., 2012) has been defined by exclusion as excessive tiredness that is not associated with sufficient ancillary symptoms to meet the CDC criteria for ME/CFS (Steele et al., 1998; Reeves et al., 2007; Son, 2019). ROC analysis provided thresholds to define CIF from the sedentary controls in quadrant analysis: Chalder Fatigue ≥17, CISR ≥5/6, MDFI General Fatigue ≥15 and sum ≥65, SF36 Vitality ≤ 33, CFSQ Sleep ≥2.5 (range 0–4), Cognition ≥1.5, and PEM ≥1.5 (Table 8). Dolorimetry and tender point counts were not effective (AUC < 0.8). McGill, other pain scores, and interoceptive complaints were not significantly different from SC. CIF individuals may have other complaints, but these were not consistent across all CIF subjects. Therefore, CIF can be defined by chronic persistent moderate or severe fatigue lasting longer than 6 months and associated with impaired vitality, sleep, cognition, and exertional exhaustion (Alexander et al., 2010; Matura et al., 2018).

Another novel finding was that 81% of CIF met CMI criteria. CMI requires two of the following: fatigue, cognition/mood symptoms, or musculoskeletal pain. The fatigue, cognition, sleep, PEM, and reduced vitality in CIF contributed to the overlap with CMI (Table 8). The CMI criteria were originally created based on the presence or absence of symptoms without regard to severity in Gulf War veterans [Fukuda et al., 1998; Centers for Disease Control and Prevention (CDC), 1995] but were found to have low specificity (Duong et al., 2022). The Kansas Criteria improve specificity for GWI by testing a larger number of symptoms (Shine et al., 2014). Requiring moderate or severe severities rather than just the presence of a symptom (i.e., mild complaints) improves specificity, as shown for the SEID, Kansas, and CFSQ for Fukuda criteria. Requiring impaired quality of life by specific SF36 domain scores is another valuable structure for a more specific diagnosis.

ME/CFS and CIF had equivalent scores for Chalder, CISR and MDFI fatigue measures. However, ME/CFS had higher scores than CIF for McGill Total and Sensory scores and the ancillary items of the CFSQ. Interoceptive and disability scores for CIF were intermediate between control and ME/CFS, classified by quadrant analysis. Although the differences were significant, ROC showed AUC < 0.78 with poor sensitivity and specificity that precluded setting thresholds to distinguish CIF from ME/CFS (Supplementary Table S14).

ME/CFS was distinguished from SC by ROC for Chalder Fatigue ≥16.5, MDFI General Fatigue ≥15.5 and sum ≥65, CMSI ≥22.5 and ≥11.5 for the no pain construct, COMPASS Sum ≥23.5, Pupillomotor ≥1.8, and McGill Total score ≥5.0, Sensory score ≥4.0, and Affective score ≥0.5 (Supplementary Table S15). ME/CFS subjects can differ in their symptom profiles, so these thresholds should be used as guidelines and verified by larger studies.

GWI was readily distinguished from SC by differences in many scores and ROC thresholds (Supplementary Table S20). Separating GWI from ME/CFS could be more of a challenge given the symptom overlap. However, GWI had more severe complaints on the McGill pain, CMSI interoceptive and GI domain, Irritant Rhinitis, and MPTSD questionnaires (Supplementary Table S14). The quality of pain was different in GWI, with higher complaints of punishing, sharp, shooting, sickening, stabbing, and throbbing. GWI males had higher scores for cramping, fearful, gnawing, heavy, hot burning, splitting, and tender. The higher scores for CMSI Ear&Sinus, Irritant Rhinitis, rhinorrhea, and Rhinitis Scores suggested greater sensitivity to volatile organic compounds and fine particulate matter in inhaled air that can stimulate irritant trigeminal and vagal afferent nerve endings in the nasal and tracheal airways (Baraniuk, 2008). Elevated rhinitis, sinusitis, and dyspnea scores in GWI were consistent with the designation of rhinosinusitis and asthma as presumptive diagnoses eligible for disability by the Department of Veterans Affairs.⁴ The GI scores were consistent with higher rates of irritable bowel syndrome in GWI than in ME/CFS.

Although no individual psychological domains were significantly different between GWI and ME/CFS, PCA component 1 for GWI females and males contained anxiety, catastrophizing, and anhedonia. Psychological symptoms did not correlate with tenderness, suggesting that central sensitization mechanisms had little direct impact on emotional, psychological, and limbic processes. As a result, we postulate that antinociceptive mechanisms act in the midbrain and medulla below the supratentorial level of cerebral and subcortical centers.

The relevance of these symptom complexes can be inferred by following the afferent innervation from somatosensory and visceral origins. Sensations from the airway, carotid sinus, cardiac, gastrointestinal, and urinary organs are conveyed by polymodal Type C and A delta afferent fibers via cranial nerves III (oculomotor), V (trigeminal ganglia), VII (facial), IX (inferior glossopharyngeal ganglion), and X (vagal nodose ganglion; Prescott and Liberles, 2022), sympathetic afferents, and spinal general afferent nerves (Christianson and Davis, 2010). They convey chemosensory and stretch information from vessels and hollow viscera. The ascending internal or “interoceptive” visceral afferents (Sherrington, 1911; Craig, 2002; Garfinkel et al., 2017) synapse in the brainstem glossopharyngeal, vagal solitary tract, paratrigeminal nucleus (Driessen, 2019), trigeminal cervical spinal columns, and other nuclei. Vagal afferents primarily carry mechanoreceptor and chemosensory sensations related to the contraction and dilation of hollow viscera and local mucosal and intralumenal environments. Inputs are projected to the insula and cingulate cortex for conscious perception according to the Embodied Predictive Interoception Coding model (Khalsa et al., 2018). They provoke subliminal reactionary brainstem autonomic and other motor reflex responses (Berntson and Khalsa, 2021).

Spinal interoceptive afferents carry signals related to temperature, pain, and tissue injury and synapse in lamina I of the dorsal horn. Secondary interneurons rise in autonomic spinothalamic columns to the ventromedial medulla, parabrachial nucleus, periaqueductal gray, catecholamine cell groups, and ventromedial posterior thalamic relay nucleus, which in turn projects to the dorsal posterior insular cortex (interoceptive cortex; Craig, 2007). Multimodal sensory projections are integrated in the middle insula and reprojected to subcortical hypothalamus and amygdala centers of homeostatic control (Craig, 2007). Stronger salient inputs trigger the anterior insula and limbic cortical regions of the anterior cingulate and orbitofrontal cortex that are part of the salience network (Menon, 2011) and then the dorsolateral prefrontal cortex and executive control network for contextual planning. Under normal circumstances, there is no need for conscious awareness of interoceptive afferent sensations or the homeostatic functions. It is likely that the innervation is tightly regulated by as yet poorly defined antiinteroceptive systems so that only moderate or severe stimuli of visceral injury or obstruction can arouse awareness in higher brain centers. There is a spectrum of interoceptive self-perception, as some people readily perceive visceral sensations such as heartbeat. It will be of interest to find if those control subjects with intermediate dolorimetry thresholds have increased self-perception. Defects of anti-interoception may allow the persistence of interoceptive sensory perception and contribute to functional somatic sensory syndromes that become attributed to dysfunction of peripheral organs.

There appear to be several parallel antinociceptive mechanisms; it is not clear if antinociceptive systems also regulate interoceptive pathways or if there are separate, specific antiinteroceptive systems devoted to the regulation of interception. Incoming interoceptive sensory signals are monitored by the ascending arousal network nuclei in the medulla and midbrain periaqueductal gray, which are designed to detect and respond to existential threats and trigger threat responses (Bracha, 2006). Threatening interoceptive, nociceptive, and exteroceptive inputs alert the periaqueductal gray and reticular nuclei, which in turn arouse ascending neurons from the locus coeruleus, dorsal raphe, ventral tegmental area, and parabrachial complex. These neurons release their respective noradrenergic, serotonergic, dopaminergic, and cholinergic amine neurotransmitters broadly throughout the cerebrum to heighten attention to the perceived threat. They also have caudal projections that may contribute to antinociceptive and antiinteroceptive pathways. The sensory consequences of a broken sensory filter are unfettered, excessive subcortical, and insula activation with enhanced perception of visceral sensations by higher centers of conscious awareness (Baraniuk et al., 2022). The salience network, hypothalamus, subcortical, and other brain regions are activated to plan and initiate protective actions such as sheltering, guarding, withdrawal from pain-provoking activities, and other defensive and self-preserving “sickness behaviors” (Bracha, 2004). Chronic persistent perception of subthreshold interoceptive sensations and activation of the reactive responses may contribute to anxiety, depression, sleep disorders, and posttraumatic stress disorder (PTSD; Berntson and Khalsa, 2021; Cao et al., 2024; Bracha et al., 2005).

The descending antinociceptive network from the midbrain and brainstem involves opioid, dopamine, serotonin, calcitonin gene-related peptide, and other antinociceptive mechanisms (Cao et al., 2024; Condon et al., 2024). One pathway originates in the periaqueductal gray (PAG) matter in opioid-responsive pain-monitoring neurons (Tobaldini et al., 2018) that descend to innervate the rostral ventromedial medulla (RVM; Figure 12). The RVM contains populations of pain “ON” neurons that are inhibited by opioids and pain “OFF” neurons that are activated by opioids (De Preter and Heinricher, 2024). One subset of glutamatergic “OFF” neurons expresses brain-derived neurotrophic factor (BDNF) and descends to the spinal dorsal horn, where they activate interneurons expressing the BDNF receptor, tropomyosin receptor kinase B (TRKB; Fatt et al., 2024). The TRKB interneurons release gamma-aminobutyric acid (GABA) and galanin that inhibit spinal processing of injurious mechanical afferent sensory neurons to prevent pain transmission. Dysfunction of this central nociplastic pathway would permit increased dorsal horn transmission of pain sensations, widespread hyperalgesia, and central sensitization. It remains to be determined if this opioid-sensitive pathway inhibits interoception or if there are additional parallel mechanisms. Understanding mechanisms of central sensitization may lead to new concepts for therapies (Arendt-Nielsen, 2015). BDNF derived from microglia and neurons in the hippocampus, parabrachial nucleus, and locus coeruleus also contribute to central sensitization (Merighi, 2024).

We anticipate that future animal studies of midbrain and brainstem sensory and autonomic regulation will reveal additional feedback mechanisms that may be generalized or more specific for pain vs. interoception.

The Central Fatigue Hypothesis (Meeusen et al., 2006) implicates serotonin and possibly dopamine pathways as braking systems that act to prevent exertion that exceeds the limits necessary to maintain homeostasis during exercise (Meeusen et al., 2006). These brakes will stop effort and exertion when neurocognitive reserves are threatened and will generate a perception of fatigue, negative reward (disincentive; Bonnelle et al., 2015), loss of motivation (Vassena et al., 2017), or apathy (Starkstein and Brockman, 2018) to complete the task at hand (Noakes, 2012). From a physiological perspective, molecular mechanisms of mitochondrial energy deficits, inflammation with elevated IL6 and TNF, oxidative stress, hypothalamic-pituitary adrenal axis dysfunction, autonomic dysfunction, obesity and adipokine inflammation, and other processes may contribute to fatigue in a wide variety of chronic autoimmune, neoplastic, infectious, cardiac, pulmonary, joint, brain, kidney, and other disease settings (Matura et al., 2018). These diseases are important exclusions for ME/CFS and GWI and can account for up to 78% of potential patients in case series evaluated for chronic fatigue (Vincent et al., 2012). Chronic fatigue increases with advanced age and is associated with frailty and mitochondrial dysfunction (Alexander et al., 2010), but it is not known if this mechanism also applies to the younger CIF subjects defined here.

The nociplastic hypothesis provides a single mechanism to explain widespread pain. The alternative is to propose widespread peripheral inflammation as a cause of whole-body nociceptive pain. We propose that a comparable antiinteroceptive system controls conscious perception of “autonomic” and visceral signaling. Compromise of this inhibitory system would lead to the wide range of internal sensations that have previously been considered separate independent functional somatic syndromes emanating from specific body systems. Instead, interoplastic pathology and reduced antiinteroceptive function would allow simultaneous conscious perception of a wide gamut of internal discomforts. This unifying hypothesis helps to explain the comorbidities of migraine, tinnitus, irritant non-allergic rhinitis, chronic cough, dyspepsia, irritable bowel syndrome, irritable bladder syndrome, and other conditions.

This hypothesis does not negate immune, autoimmune, microbiome, metabolomic, mitochondrial, or neurotoxic pathologies that may initiate brain or peripheral organ injury and exacerbate the sensory perceptions. These pathological mechanisms may also affect the midbrain and brainstem pathways and initiate the interoplastic and nociplastic dysfunction. The same reasoning can be applied to the new epidemic of Long COVID (Fernández-de-Las-Peñas, 2022). COVID infection in humans and murine models leads to elevated CCL11 (eotaxin) that is associated with hippocampal and other microglial activation, loss of oligodendrocytes, brain demyelination, structural changes (Douaud et al., 2022), and cognitive dysfunction (Fernández-Castañeda et al., 2022). Cognitive dysfunction in ME/CFS, GWI, and “COVID fog” has parallels with fibromyalgia cognitive dysfunction (“fibro fog”), cancer therapy-related cognitive impairment (“chemo fog”) that follows brain radiation, methotrexate and other chemotherapeutic agents, and low-dose lipopolysaccharide models of systemic inflammation (Geraghty et al., 2019; Gibson and Monje, 2021). Elevated eotaxin, aberrant microglial pruning of synapses, reactive astrocytes, oligodendrocyte cell death, and BDNF expression may contribute to a common final pathway for cognitive dysfunction (Polli et al., 2020). BDNF may also be dysregulated in exercise and post-exertional malaise (Venezia et al., 2017). Understanding the symptomatology of these diseases and correlation with molecular mechanisms of pathology will cross-fertilize investigations for all of these nociplastic, interoplastic, fatiguing illnesses (NIFTI) and may provide insights into new therapies (Ayoub et al., 2020; Acharya et al., 2016).

About one quarter to one third of military personnel exposed to the conditions of the Persian Gulf War have developed unremitting GWI. About 1% of the general population have had sudden onset viral-like syndromes or gradual onset of unremitting ME/CFS symptoms. In both cases, subjects consider it a mystery as to why they got sick and do not get better. Their reflections on the constancy and permanence of the symptoms have been interpreted as rumination. They have often been told that “it is all in your head” (Timbol and Baraniuk, 2019). The lack of empathy and therapies engenders frustration, anxiety, irritability, and a sense of helplessness. The fatigue, severe pain, unexplained interoceptive complaints, and exertional exhaustion preclude involvement in activities that were previously enjoyable (anhedonia). These psychological constructs describe the reality of ME/CFS, GWI, and Long COVID and are often mistaken for depression.

An alternative approach to this conspiracy of nomenclature and symptom salad (Figure 1) is to re-consider the psychic symptoms in GWI and ME/CFS as “motivational anhedonia” that is characterized by deficits in reward motivation, strongly impaired quality of life (Whitton et al., 2023), fatigue and lack of energy (Treadway and Zald, 2011; Felger and Treadway, 2017; Billones et al., 2020; Daumas et al., 2022). Elements of fatigue, anhedonia and apathy are correlated but are not synonymous. The central pathology of motivational anhedonia involves altered processes for valuation of cognitive and physical efforts when contrasted with potential positive rewards vs. inevitable punishing symptom exacerbation and relapse (PEM; Haber and Knutson, 2010; Treadway and Salamone, 2022; Cooper et al., 2018). Motivational anhedonia is linked to dysfunction of dopaminergic corticostriatal reward networks in the putamen, dorsal anterior cingulate cortex (dACC) and surrounding paracingulate and presupplementary motor areas (Figure 12; Pizzagalli, 2022; Tye et al., 2013; Husain and Roiser, 2018). These regions are critical hubs for effort-based decision-making (Arulpragasam et al., 2018; Bonnelle et al., 2016; Lopez-Gamundi et al., 2021; Walton et al., 2003; Rudebeck et al., 2006), evaluation of the cost of efforts (Westbrook et al., 2019) and consideration of the difficulty of tasks (Shenhav et al., 2014). We can anticipate that appropriate provocation studies with magnetic resonance imaging in ME/CFS and GWI will demonstrate dorsomedial prefrontal dysfunction or altered functional connectivity between the ventral striatum and ventromedial prefrontal cortex (Bekhbat et al., 2022). The dACC is a major hub of the salience network (Menon, 2011) that may be enlarged in persons at risk for major affective disorders such as depression (Lynch et al., 2024). Enlargement of salience nodes and overactivity of attention and vigilance networks may contribute to the continuous threat assessment, motivational anhedonia and increased scores on psychological and other questionnaires in GWI and ME/CFS. This pathomechanism is relevant to major depression where about one third of cases have an inflammatory phenotype with CRP levels >3 mg/L and respond to infliximab, a monoclonal antibody that antagonizes tumor necrosis factor alpha (TNFa; Treadway et al., 2024). About a third of our subjects had elevated CRP and possible motivational anhedonia suggesting that infliximab may be a viable experimental therapy for a “neuroinflammatory” phenotype of ME/CFS and GWI. Before considering motivational anhedonia as a component of ME/CFS and GWI it is necessary to demonstrate fMRI evidence of dysfunctional prefrontal striatal connectivity during tasks of reward discounting.

The rate of PTSD in this cohort is higher than in other studies (Weiner et al., 2011; Richardson et al., 2010). Emerging data indicate that the subgroup of GWI with PTSD may have more severe disease with aggravating pathological features (Sultana et al., 2024; Jeffrey et al., 2021). This places a large onus on the Department of Veterans Affairs medical system to incorporate questionnaires such as the MPTSD, PCLC, PCLM, and Kansas questionnaire into routine medical practice to improve diagnosis and expand healthcare for veterans at risk. A lack of insightful care will promote a sense of frustration in veterans and withdrawal from the medical system, potentially leading to self-medication and the morbid cycle of suicidality.

This analysis has limitations. The sample sizes were small and unbalanced after accounting for gender and CIF subsets. Verification of the current findings will require larger sample sizes, but the raw data, means and standard deviations, Hedges' g, and Spearman correlation values provide effect sizes that can be used to power future studies appropriately. However, larger studies may find smaller effect sizes than those inferred from the current results (Owens et al., 2021).

Bonferroni corrections for multiple comparisons were employed to correct for the large number of questionnaire domains that were compared. Spearman correlations with |R| > 0.5 were required for consideration of association, but do not demonstrate causality. The ROC thresholds provide guidance for diagnosis but only if the analysis is sufficiently significant. The speculative mechanistic inferences are hypotheses for future testing and to stimulate fresh insights.

Confounding factors were excluded by univariate general linear modeling with age, race, Hispanic status, body mass index (BMI), PTSD, Type II diabetes mellitus, and FM by 1990 criteria. Other comorbidities or underlying conditions may still be discovered that impact tenderness and central sensitization in ME/CFS and GWI. Additional factors such as atypical depression, drug abuse, cellular senescence, occult cardiovascular issues, infectious diseases, cancer, or other chronic diseases may contribute to CIF and will have to be evaluated in future studies.

The gender differences for dolorimetry (Figures 7, 9, Table 1) and other objective outcomes in ME/CFS (Cheema et al., 2020; Gamer et al., 2023; Jeffrey et al., 2019) demonstrate that sexual dimorphisms must be evaluated for all study outcomes before generalizing across genders for all subjects. We evaluated this limitation by assessing genders separately for differences in means between ME/CFS, GWI, and control, PCA, and Spearman correlations (Supplementary material). Women had greater nociplastic sensitivity, but questionnaire outcomes were more similar between sexes. Although interoceptive scores were similar between genders, correlations with objective mechanisms may differ, as suggested by higher correlations for women between interoceptive Self-Awareness Questionnaire scores and brain functional connectivity in salience and frontal-parietal executive control networks than for men (Alfano et al., 2023). Menopause represents another important variable to assess because of differences in nociception and dorsal horn gene regulation in animal models of males and oophorectomized females compared to fertile females (Dedek et al., 2022).

Assigning subjects into diagnostic groups tends to restrict the range of symptom scores they experience. Controls have few symptoms, indicating floor effects for correlation. Designation of CIF requires that fatigue be moderate or severe, so the full range from none to severe was not available for correlations. Dolorimetry pressures were similarly skewed to lower ranges in ME/CFS and GWI. The ceiling and floor effects greatly reduced the mathematical possibility of finding significant correlations. Pain, interoception, migraine, and disability were still significantly correlated with tenderness across the various groups and in both sexes. The explained variances were low, indicating that other variables or confounders contributed to the relationships but were not revealed by age, gender, body mass index, and questionnaire topics. Dolorimetry and interoception were correlated, but with a low, yet still significant, explained variance, indicating that nociplastic mechanisms contributing to pain had some overlap with interoceptive mechanisms regulating perceptions derived from vagal and other internal visceral sensing systems.

ME/CFS and GWI have different disease etiologies but share similar patterns of differences from control nociceptive, interoceptive, and other questionnaire outcomes. The average dolorimetry pressures and ROC analysis did not separate ME/CFS from GWI. This suggests that diverse initiating inflammatory or neurotoxic exposure events may be followed by shared “final common pathways” that produce central sensitization and similar symptomatic and tenderness disease manifestations. Future studies of long COVID will provide an additional “illness control,” where we predict central sensitization will lead to a comparable suite of dolorimetry, symptoms, and questionnaire scores.

Tenderness was demonstrated in ME/CFS, which makes it difficult to differentiate fibromyalgia using the 2010 and 2019 criteria. Future studies should report dolorimetry or other evidence of central sensitization in order to exclude fibromyalgia and study “pure” ME/CFS. However, our hypothesis of shared antiinteroceptive and antinociceptive mechanisms weakens the possibility of dichotomizing ME/CFS vs. ME/CFS/fibromyalgia. Univariate models that include dimensions of fatigue, pain, tenderness, and other outcomes are likely to be better statistical approaches. Our GWI cohort was more tender than others [e.g., an average of 6 tender points, 28% with ≥11/18 tender points (Steele et al., 2021)].

The separation of sensations into interoceptive and nociceptive is a reasonable starting point for sensory analysis but is likely to be simplistic. Additional sensory modalities, such as pruritogenic, thermal, and piezomechanical, exist that have not been as well characterized for increased central perception in ME/CFS, GWI, or other diseases with central sensitization (Dunphy et al., 2003). Sensory modalities are mediated by over two dozen subclasses of small-diameter unmyelinated and large myelinated dorsal root ganglion, trigeminal, and vagal nodose and jugular ganglion neurons (Kupari et al., 2019; Yu et al., 2024; Nguyen et al., 2017). These fiber types exhibit diverse properties, including differential presynaptic inhibition by opioid mu, delta, and kappa receptors, transcription factors, and mRNA expression. Each may have specific descending inhibitory neural pathways or other means of sensory regulation. Future investigations may identify specific inhibitors for these modalities and correct nociplastic, interoplastic, and other dysfunctional neural signaling mechanisms.

Inclusion of Common Data Elements, such as quality of life instruments, in published reports will improve data sharing for study design and power calculations (Cohen et al., 2022; Slavin et al., 2023; Grinnon et al., 2012). The questionnaires were chosen to assess fatigue, quality of life, pain, interoception, and psychological constructs, but the strongest correlations were within questionnaire domains rather than with fatigue or other indices. It is not clear if newer questionnaires that have been introduced since the start of data collection will improve the potential for correlated outcomes and specificity in ME/CFS and GWI. There is significant overlap of items with similar wording but different interpretations between different questionnaires that may lead to confusion about the validity of underlying latent factors. Despite this, there was surprisingly poor correlation between fatigue scales (Chalder, CISR, MDFI, Epworth). Questionnaires with more items and levels of severity appeared to be superior to those with dichotomous present/absent or yes/no answers. As a result, the Kansas criteria provide more information than the CMI classification. ME/CFS and GWI have many complaints with high severity, leading to wide ranges and large variance ceiling effects, but are in contrast to SC, who have minimal symptoms, narrow ranges for SD, and floor effects. Different questionnaires will be required to bypass the ceiling effects when studying the most severe ME/CFS cases.

The volunteers made active decisions to participate and were thus a motivated self-selected group who may have been seeking assistance and insight into their personal experiences, as opposed to subjects who have withdrawn from contact and did not participate. Population-based studies will be necessary to confirm our findings. One way to access the population is for medical providers and the VA medical system to incorporate the Kansas, DePaul, and MPTSD instruments into electronic medical records dashboards in order to cue doctors to investigate these diagnoses and educate doctors and patients who are familiar with GWI or ME/CFS about their disease. The exercise will generate clinical databases for further study.

The clinical criteria for both diseases continue to be challenging for clinicians. Precise case designation criteria must be applied in research manuscripts. Requiring moderate or severe complaints will improve diagnostic specificity and reduce the false positive impact of CIF and other diseases that feature fatigue. This will also apply to the overlap of functional somatic syndromes such as IBS, where central sensitization is inferred. Tenderness should be stringently measured in these other disorders in order to understand the holistic spectrum of bodily complaints, personal impairments, and coping strategies. The correlations are a starting point for planning new studies of shared deficits in fMRI, metabolomics, gut microbiome, and other mechanistic outcomes to bridge the gap between subjective and objective testing in order to define mechanisms of disease, clinical biomarkers, and diagnostic tests.

We demonstrate that people with ME/CFS and GWI have tenderness. Even though we did not define strong criteria for specific numbers of tender points or dolorimetry thresholds, it is clear that the general finding of systemic tenderness is consistent with these diagnoses and their symptom profiles. Animal models are revealing new antinociceptive pathways, but there is much less research into interoception and antiinteroceptive mechanisms. Future studies can be powered using the outcomes reported here (Supplementary Table S20). Our outcomes can also be used to define CIF. On a practical note, we advocate testing for tenderness by physical examination as an adjunct to the published symptomatic criteria. Future provocation methods may be developed that can be readily used in the clinic to investigate the finding of central sensitization and to demonstrate that lower levels of provocation can lead to exaggerated levels of complaints (i.e., tenderness).