Understanding the relationship between chronic pain and emotional disorders

Tadjibaev, Arman (2021) Understanding the relationship between chronic pain and emotional disorders. PhD thesis, University of Nottingham.

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Abstract

Although frequent coexistence of chronic pain and emotional disorders is well documented, exact mechanisms of comorbidity are not fully understood. The overarching aim of this thesis was to advance our knowledge of the mechanisms that link chronic pain and emotional disorders.

Results of the literature review suggest that nosologically different conditions might coexist if they share common transdiagnostic risk factors that predispose individuals to several disorders. Using this transdiagnostic approach, a theoretical model explaining the relationships between different risk factors and how they might contribute to comorbidity between chronic pain and emotional disorders has been developed. According to the proposed model, one of the most fundamental transdiagnostic risk factors associated with both conditions is uncontrollable stress. It does not cause chronic pain or emotional disorders directly but promotes development of other risk factors, such as helplessness, negative affectivity, hypersensitivity to pain, dysregulation of stress response, and cognitive deficits. Importantly, these risk factors are not disorder specific. They equally predispose individuals to depression, anxiety, and chronic pain. Development of a specific disorder is determined by the influence of environmental and biological moderators that transform pre-existing risk factors into specific disorders.

Considering that the sequence of pathological processes leading to psychopathology and/or chronic pain starts from the experience of uncontrollable stress, it is important to identify neural mechanisms that could mediate its effects. There is evidence suggesting that the frontal pole comprising of the rostromedial prefrontal cortex (rmPFC) and rostrolateral prefrontal cortex (rlPFC) plays an essential role in evaluation of controllability. Dysfunction of this area may increase the sense of uncontrollability, thereby promoting development of transdiagnostic risk factors. Both subregions of the frontal pole are parts of the neural networks that perform higher-order processing and modulation of nociceptive and emotional reactions. Thus, increased sensitivity to pain and heightened negative affect in patients with chronic pain disorders might be mediated by impaired interaction of the rmPFC and rlPFC with low-level nociceptive and emotional circuits.

To test this hypothesis, resting-state functional and effective connectivity of the rmPFC and rlPFC was investigated in two chronic pain conditions: chronic low back pain (CLBP) and osteoarthritis (OA).

Functional connectivity (FC) of the rmPFC and rlPFC in CLBP. CLBP patients displayed decreased FC of the rmPFC with retrosplenial cortex (RSC), posterior part of the ventral pallidum (VP), and mediodorsal (MD) thalamus. Diminished interaction with these regions may hinder retrieval of positive episodic memories of control and attribution of positive outcomes to personal actions. This may negatively influence patients’ belief about their ability to cope with stress, increase the sense of perceived uncontrollability. CLBP patients also showed reduced FC of the rmPFC with the medial pulvinar nucleus of the thalamus, midbrain reticular formation, and periaqueductal grey. These structures are parts of the ascending reticular activating system (ARAS) that regulates the level of arousal in the central nervous system. Reduced modulation of the arousal system by the rmPFC may result in development of a hyperarousal state and amplification of nociceptive and emotional responses leading to hyperalgesia and increased negative affectivity. There was no difference in FC of the rlPFC between CLBP patients and healthy controls.

Effective connectivity analysis in CLBP. Causal interactions between the rmPFC, stress-related brainstem structures (dorsal raphe nucleus, ventral and dorsal periaqueductal grey), and memory systems (ventral striatum, hippocampus, amygdala) were investigated using the spectral dynamic causal modelling (spDCM). Consistent with the results of the FC analysis in CLBP, the spDCM also found altered interaction between the rmPFC and memory systems. Specifically, patients showed weaker connectivity of the rmPFC with hippocampus and stronger connectivity with the amygdala. Such pattern of connectivity may lead to inaccurate evaluation of the probability of control based on past experiences, overgeneralization and impaired extinction of fears. Patients also demonstrated hyperactivation of the dorsal raphe nucleus, ventral and dorsal periaqueductal grey (parts of the ARAS) that may contribute to hyperalgesia and increased negative affectivity.

Functional connectivity of the rmPFC and rlPFC in OA. In this study FC of the rmPFC and rlPFC was compared between patients with shorter duration of OA (<7 years), patients with longer duration of OA (>7 years), and healthy volunteers. Only patients with longer duration of OA showed increased negative FC of the rmPFC with multiple brainstem nuclei, such as the parabrachial complex, locus coeruleus, dorsal and median raphe nuclei, ventral tegmental area, midbrain reticular formation, and periaqueductal grey, that together comprise the ARAS. Negative FC between the rmPFC and ARAS may reflect increased compensatory inhibition of the activating system by the rmPFC in attempts to suppress pain-induced arousal and negative affect. Despite longer duration of pain, patients did not show signs of hyperalgesia or emotional distress. Perhaps, effective suppression of the brainstem arousal system demonstrated by OA patients was due to preserved connectivity between the rmPFC and memory systems. Both groups of OA patients also showed reduced FC of the rlPFC with the multiple demand network that may contribute to development of another transdiagnostic risk factor, i.e., cognitive deficit.

Results of all three studies presented in this thesis suggest that chronic stress may cause development of transdiagnostic risk factors such as negative affectivity and hyperalgesia via hyperactivation of the brainstem arousal system that augments nociceptive and emotional responses. Impaired regulation of the arousal system by the rmPFC, which evaluates controllability of the stress based on previous experiences, may contribute to hyperactivation of the ARAS. Reduced interaction between the rmPFC and memory systems may obstruct retrieval and utilization of positive memories of control, thereby increasing the sense of uncontrollability, facilitating hyperarousal, and contributing to development of transdiagnostic risk factors. In contrast, preserved connectivity between the rmPFC and memory systems may oppose the negative effects of chronic stress and help patients to maintain a belief that they are capable of coping with the stress.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Auer, Dorothee
Hodkinson, Duncan
Keywords: Chronic pain, Emotional disorders
Subjects: R Medicine > RB Pathology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 66157
Depositing User: Tadjibaev, Arman
Date Deposited: 31 Dec 2021 04:40
Last Modified: 31 Dec 2021 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/66157

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