The High-Risk Model of Threat Perception Modulates Learning of Placebo and Nocebo Effects and Functional Somatic Disorders
Abstract
1. Introduction
2. Is Paradoxical Skin Temperature Increase (PTI) During Threat Perception in Chronic Pain Linked to Dysregulation of the ANS?
3. The HRMTP Modulates Functional Somatic Disorders and Placebo and Nocebo Somatic Effects
“Sometimes it is more important to know what kind of patient has a disease than what kind of disease the patient has.”—Sir William Osler
- A. Predisposing Risk Factors Modulating Threat and Pain Perception
- 1.
- Trait hypnotizability–suggestibility [65,66,67,71,110], related trait Absorption [111] and trait Alexithymia [27,72,75,78] are three closely related personality trait factors that are postulated by the HRMTP to be psychosocial personality mechanisms modulating (1) ANS reactivity during threat (HPAA) and pain perception, (2) the generation of somatic placebo and nocebo effects and (3) FSD [55]. Specifically, it is postulated [24,26,27,33] that these three related personality traits, (1) hypnotizability–suggestibility, (2) Absorption and (3) Alexithymia, despite varied labels, all empirically converge to modulate human threat perception (HPAA) and pain perception and to modulate FSD [55].
- 2.
- High learned catastrophizing [24,28,30,112,113,114,115,116,117] is explicit or implicit verbal responses to threat that reliably amplifies threat and pain perception and is measured by verbal report psychometric scales [27,114] and also apparently manifests in EEG effective connectivity measures [113]. Amygdala functional connectivity in fMRI data mediates the association between catastrophizing and threat-safety learning in chronic pain in youth [16].
- 3.
- High trait Neuroticism or Negative Affectivity (NA) [24,30,36,38,86,112,118,119] is a predisposition to amplified threat perception, independent of objective negative events. Trait or state NA can be measured with psychometric measures [86] or by the electrodermal response—EDR [36,38,83], and state NA appears associated with the default mode network (DMN) in chronic low back pain [85]. Nocebo effects are linked to high NA as a risk factor [116]. High NA is robustly related experimentally, even to the common cold ([120], NEJM) and medical illness with identified pathophysiology [121].
- 4.
- High trait Self-Deception (SD) is a trait tendency to interpret negative events or threats positively [30,33,112]. SD is measured with a High Marlowe Crowne score [122,123] or another psychometric measure of social desirability. High SD is a >17 score on the Marlowe Crowne psychometric scale and is a measure of repressed threat perception unrelated to the complex Weinberger hypothesis [122,124].
- B. Triggering Risk Factors Modulating Threat or Pain Perception
- 1.
- 2.
- The density and intensity of Daily Hassles: Accumulation of Daily Hassles inducing threat in some people activates the hypothalamic–pituitary–adrenal axis and can be associated with mortality and morbidity [24,30,33,129]. Hassles are measured with several psychometric scales of known reliability and validity.
- 3.
- C. Buffering Risk Factors Modulating Threat or Pain Perception
- 1.
- High social support [24,26,30,33,99,100,133] is measured by several verbal report psychometric scales and is reliably correlated with many physical diseases, including cardiovascular and cancer diseases, in replicated studies of morbidity and mortality mediated by threat (HPAA) and other neuroendocrine measures.
- 2.
- Approach and Avoidance Coping Skills [133,134,135] are measured by Approach and Avoidance psychometric scales [136] and are related to amplified Approach Coping Skills in positive mental and physical health outcomes [133]. Two-factor learning theory [27] predicts that avoidance behavior [137] is associated with many mental disorders and avoidance coping is postulated to be associated with FSD, specifically chronic pain [27,32,138]. Approach coping and placebo effects are associated with “safety cues” and fear extinction [27,139] and reduced somatization and reduced FSD.
- 3.
- High positive affectivity [30,140,141,142] is measured with several psychometric verbal report scales and is reliably related to positive mental and physical clinical health outcomes [140]. High positive affectivity appears to buffer nocebo effects [141]. Two studies [141,142] recently confirmed the HRMTP’s prediction that experimentally induced trait or state positive affectivity would buffer or reduce nocebo effects.
4. Primary Predisposing Risk Factor Trait Hypnotizability–Suggestibility Modulates Threat Perception (HPAA) and the Expression of Other Predisposing, Triggering and Buffering Risk Factors
4.1. Predisposing Risk Factor Trait Hypnotizaiblity and Blood Pressure Reactivity in the ICU from Cadiac Bypass Surgery
4.2. Predisposing Risk Factor High and Low Hypnotizability Is Associated with Distinct Patterns of ANS Reactivity to Threat Induction
4.3. Primary Predisposing Risk Factor Trait Hypnotizability–Suggestibility, Definition and Parameters
4.4. ANS Reactivity and Functional Somatic Disorders (FSDs)
5. Can Automaticity and Reduced Sense of Self Agency in High Hypnotizable (HH) Patients Exponentially Amplify Threat Perception?
5.1. Trait Hypnotizability–Suggestibility and Related Trait Absorption (TAS) Modulate Learned Placebo and Nocebo Effects and Functional Somatic Disorders
5.2. Trait Absorption (TAS) and Functional Somatic Disorders
5.3. Predisposing Risk Factor Trait High Alexithymia Is Correlated Negatively with Low Hypnotizability and During Threat-Induced Functional Somatic Disorders
6. Is Pavlovian Learning of Biologically Embedded Threat Perception Modulated by the Predisposing, Triggering and Buffering Risk Factors of the HRMTP?
“Stress is a state of mind, involving both the brain and body as well as their interactions; … it also reflects stable epigenetic modifications in development that set lifelong patterns of physiological reactivity and behavior through biological embedding of early environments interacting with cumulative change from experiences over the lifespan.”(McEwen, 2012, PNAS, p. 17180 [6])
7. Are Predisposing Risk Factors Linked to Triggering Risk Factors of the HRMTP?
Respiratory Heart Rate Variability [19] Learning Activates and Modulates the Vagal Brake in Emotional Learning
8. Frequency of Functional Somatic Disorders in Primary Care Medicine and the Risk of Unintentional Iatrogenic Injury in the Invasive Medical–Surgical Hospital Context
“Pain syndrome patients, in their desperate search for the elusive cure, often chase “windmills” and convince their doctors to perform a myriad of invasive tests, and procedures. As a result of their pain behaviors, many experience iatrogenic complications, suffering and disability.”—G.M. Aronoff, MD Editor, Clinical Journal of Pain, 1(1) 1985 [251].
Two Subsets of Patients at Risk for Unintentional Iatrogenic Injury
9. The Conditioned Response Model (CRM) of Emotional Learning of Placebo and Nocebo Somatic Effects and FSD
- Positive or negative verbal suggestion is postulated by the CRM to induce placebo or nocebo somatic effects and FSD, and all invasive verbal suggestion is postulated to be modulated by the innately effective (US-UR) psychosocial active ingredient trait hypnotizability–suggestibility [33,35,36,53,54,61,154,267,270]. Two large meta-analyses found that trait hypnotizability–suggestibility modulates, in a dose–response or linear manner, the efficacy of verbal suggestions to reduce clinical and experimental threat and pain perception [39,40].
- Interpersonal delivery of rapport through accurate verbal Empathy and Warmth, are innately effective (US-UR) psychosocial active stimuli to induce and modulate placebo and nocebo somatic effects and FSD. Empirically, empathy and warmth can modulate anxiety, threat and pain perception [27,264,271,272,273,274,275,276]. It also appears that empathy is modulated by trait hypnotizability-suggestibility [247].
- The CRM predicts that the identification and application of innately effective [53,54,61,197] psychosocially active stimuli (US-UR), in the context of increasingly invasive [278] and threatening medical–surgical procedures (US-UR) on patients, can amplify the magnitude of future placebo effects in clinical trials [61,197,278,279,280,281,282,283].
- Associative learning can, through neutral stimuli (CS), automatically and unconsciously [222,223] trigger activation or deactivation of previously learned (e. g., adverse childhood experiences and traumatic major life changes like the injury or death of a parent) and biologically embedded nocebo effects [6,7,28,29,31,35,37,54,56,228] through epigenetic mechanisms, like heterochromatin and Euchromatin [284,285,286].
- Trait hypnotizability–suggestibility is postulated to be an innately effective (US-UR) modulator of empathy learning [247], verbal suggestion learning and associative learning of placebo somatic effects [101,102,103,104,105,106], nocebo somatic effects [106,107,108,109] and functional somatic disorders [23,30,33,34,41,44,45].
- It is predicted by the CRM and HRMTP that chronic anomalies and incongruities [27,69,70,71] in emotional perception and emotional learning and ANS reactivity in trait low hypnotizability–suggestibility and High Alexithymia can reduce HRV [19] and increase risk of ANS dysregulation [28,30,31,35,36,79,80,81] as postulated in chronic threat and pain perception associated with allostasis and biological embedding [6,7,82].
- It is predicted that trait high hypnotizability (HH) amplifies threat perception, and that HH is a risk factor for FSD, unless the patient’s HH is mobilized specifically by verbal hypnotherapy or non-specifically by psychosocial therapies, like pain reprocessing therapy, CBT, EMDR, or biofeedback therapy.
10. Clinical vs. Experimental Contexts
11. The Psychophysiology of the Clinician–Patient Relationship and Associative Emotional Learning Modulated by Trait Hypnotizability–Suggestibility and Social Support
12. General Predictions from the CRM and the HRMTP
- The CRM predicted that as new innate specific active biological ingredients (US-UR), including psychosocial active ingredients (e.g., trait hypnotizability, empathy and warmth) for “healing” are isolated, paradoxically the placebo response can get stronger in future randomized placebo-controlled gold standard clinical trials [53,54,61]. This early prediction of amplified placebo effects in future clinical trials [53,54,61] appears to be supported today by the high reported correlation (r = 0.73) between placebo effects and pharmacological effects in recent clinical randomized controlled trials [281] predicted by Wickramasekera in 1980 and 1985. The increased magnitude of placebo effects in US clinical trials of pain and especially of neuropathic pain [282,296] support the CRM prediction. The progressive mean increases in placebo effects (40%) in Irritable Bowel Syndrome—IBS [297] are also supportive of the CRM prediction. The recent review of treatment effects in pharmacological randomized controlled clinical trials of five diseases [281] stated that the placebo effect is the “major driver of treatment effects in clinical trials that alone explains 69% of the variance” [281]. This review [281] of the efficacy of 150 pharmacological randomized controlled clinical trials found that 72% of the variance in treatment effects could be attributed to placebo effects or context effects.
- The HRMTP predicts that, in FSD patients with chronic pain, intermittent threat perception can drive dysregulation of the ANS and PTI. This prediction was apparently confirmed by the association of experimental threat induction and Paradoxical Increase in hand Temperature (PTI) in approximately 50% of 224 of chronic pain patients of both genders. This PTI was first experimentally demonstrated by Wickramasekera et al. [37] and replicated independently in a PhD dissertation [96].
- The HRMTP predicts that the primary Predisposing risk factors (a) trait hypnotizability–suggestibility, if it implicates threat learning, interacting with other HRMTP risk factors (e.g., high catastrophizing, high ACEs and low social support) can maladaptively amplify threat perception in an exponential manner and launch a progressive trajectory of severe morbidity, if not mortality.
13. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
HRMTP | High Risk Model of Threat Perception |
CRM | Conditioned Response Model |
FSD | Functional Somatic Disorder |
HPAA | Hypothalamus–Pituitary–Adrenal Axis |
ANS | Autonomic Nervous System |
PTI | Paradoxical Hand Temperature Increase |
SRSSs | Stress-Related Somatic Symptoms |
US | Unconditioned Stimulus |
UCR | Unconditioned Response |
CS | Conditioned Stimulus |
CR | Conditioned Response |
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Wickramasekera, I. The High-Risk Model of Threat Perception Modulates Learning of Placebo and Nocebo Effects and Functional Somatic Disorders. Brain Sci. 2025, 15, 955. https://doi.org/10.3390/brainsci15090955
Wickramasekera I. The High-Risk Model of Threat Perception Modulates Learning of Placebo and Nocebo Effects and Functional Somatic Disorders. Brain Sciences. 2025; 15(9):955. https://doi.org/10.3390/brainsci15090955
Chicago/Turabian StyleWickramasekera, Ian. 2025. "The High-Risk Model of Threat Perception Modulates Learning of Placebo and Nocebo Effects and Functional Somatic Disorders" Brain Sciences 15, no. 9: 955. https://doi.org/10.3390/brainsci15090955
APA StyleWickramasekera, I. (2025). The High-Risk Model of Threat Perception Modulates Learning of Placebo and Nocebo Effects and Functional Somatic Disorders. Brain Sciences, 15(9), 955. https://doi.org/10.3390/brainsci15090955