Pain and depression: cognitive and behavioural mediators of a frequent association

Literature findings

The comorbidity between chronic pain and depression is high: in the general population setting, the odds ratio for suffering from one of these disorders when suffering from the other is estimated around 2.5. For chronic pain patients consulting in pain clinics, the comorbidity rate reaches one third to half of the patients. For the International Association for the Study of Pain (IASP), pain consists in an emotional as well as a sensory dimension, both of them have to be assessed systematically. Likewise, affective disorders must be systematically depicted in chronic pain patients. The reasons for such comorbidity are complex and result from the conjunction of common risk factors (environmental and genetic vulnerability factors) and of a bidirectional causality.

The transactional model of stress and coping of Lazarus et Folkman

The appraisal stress model (Lazarus and Folkman, 1984) offers an opportunity to understand how chronic pain can cause depression. Pain is conceptualized as a chronic stress. Its appraisal in terms of loss, injustice, incomprehensibility or changes (primary appraisal), and in terms of control (secondary evaluation) determine how the subject will cope with pain. Several personality traits as optimism, hardiness or internal locus of control play a protective role on these evaluations, whereas others (neuroticism, negative affectivity or external locus of control) are risk factors for depression. Low perceived social support is also related to depression. On the contrary, self-efficiency is linked with low levels of depression. Self-management therapies focus on increase of perceived control of pain by the patient in order to improve his/her motivation to change, and to let the patient become active in the management of his/her pain.

Conclusion

According to Lazarus and Folkman (1984), coping strategies are the constantly changing cognitive and behavioural efforts to manage specific external and/or internal demands that are appraised as taxing on or exceeding the resources of the person. Pain patients can use a wide variety of pain coping strategies: problem versus emotion focused strategies or cognitive versus behavioural strategies. Some of them are highly dysfunctional, such as catastrophizing (cognitive strategy) or avoidance (behavioural strategy). Their preferential use can lead to the development of a depressive episode. The “fear-avoidance model” (Vlayen, 2000) explains pain chronicization by a vicious circle that begins with the pain catastrophizing; this leads to fear of pain, which in turn leads to avoidance and finally to pain and depression. This is why some behavioural cognitive interventions focus on the reduction of catastrophizing and avoidance. Some functional pain coping strategies were identified: they are active strategies centred on problem resolution such as distraction, reinterpretation or ignorance of pain sensations, acceptance, and exercise and task persistence. New therapeutic interventions focus on the development of better coping strategies such as distraction, relaxation and acceptance.     

Coping behaviors among depressed and nondepressed medical inpatients

Sixty medical inpatients completed a variety of psychological measures related to factors associated with depression. An analysis of self-reported depression and coping response indices revealed significant differences in coping strategies between depressed and nondepressed medical inpatients. Depressed patients more often reported avoidance strategies to cope with the stressors associated with hospitalization, while nondepressed patients were more likely to utilize active coping techniques. Since the coping and depression measures were assessed concurrently, the direction of influence cannot be determined. Still, these findings are consistent with the learned helplessness model of depression for medical inpatients and suggest specific psychological interventions for treating this population. Such treatment would attenuate the adverse effects of inpatient medical depression and thereby enhance the desired benefits of medical hospitalization. It is suggested that future research examine the effectiveness of coping in a prospective design to clarify the direction of the coping and depression relationship.     

Longitudinal course of depression symptoms in multiple sclerosis

BACKGROUND: Despite the high lifetime prevalence of depression in multiple sclerosis (MS), its longitudinal course is poorly understood. OBJECTIVE: To examine the longitudinal course of and reliable change in different depression symptom clusters in MS, and the longitudinal association of interferon beta treatment and coping with depression symptoms. METHODS: 53 MS patients were examined at two time points three years apart on the Beck Depression Inventory (BDI) and the Chicago Multiscale Depression Inventory (CMDI). RESULTS: Correlations from time 1 to time 2 for BDI, CMDI-total, CMDI-evaluative scale, and CMDI-vegetative scale were all highly significant, and reliable change indices reflected little change over time. In contrast, the correlation over time for the CMDI-mood scale was significantly lower (p<0.05) than the CMDI-evaluative and CMDI-vegetative scale correlations, and over 40% of patients showed reliable change. Patients who improved in their mood showed increased use of active coping, while patients who worsened showed decreased active coping strategies; the latter were also significantly more likely to have been taking interferon beta drugs at both time points than patients who did not change in their mood functioning. CONCLUSIONS: Mood symptoms of depression are significantly more variable over time than neurovegetative or negative evaluative symptoms in MS patients. Decreased use of active coping strategies may put patients at risk of increased depressed mood, whereas increased use of active coping may result in decreased depressed mood longitudinally. Interferon beta use may put patients at risk of increases in depressed mood.     

Cognitive impairment in multiple sclerosis does not affect reliability and validity of self-report health measures

Patient self-report health measures have received increasing recognition as supplementary outcome parameters in multiple sclerosis (MS). Given the high prevalence of cognitive problems in this population, reliability and validity of self-report instruments in patient groups with cognitive impairment is essential, especially when using such scales longitudinally. A sample of 80 MS patients with cognitive dysfunction according to Symbol Digit Modalities Test (SDMT) score and 107 unimpaired patients were included in the analyses. Data was available from the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS), the Hospital Anxiety and Depression Scale (HADS), clinical rating scores [Expanded Disability Status Scale (EDSS) and FS (Functional Status) scales, CAMBS (Cambridge MS Basic Score)] and objective tests of upper and lower limb function [Timed 8 Meter Walk (T8) and Nine Hole Peg Test (9HPT)). Both self-report questionnaires showed satisfactory internal consistencies and retest reliability. Pattern and magnitude of correlations with other health status measures supported the validity of both instruments. However, there was a marked discrepancy between subjective and objective measures of cognitive function. Cognitively impaired patients furthermore showed significantly higher depression and anxiety as well as lower quality of life (QoL). The report provides evidence that QoL and affective symptomatology can be reliably assessed in MS patients with cognitive dysfunction. The common pattern of poor correlation between self-rated and objective cognitive function thus appears to be a result of the patients' (adaptive or maladaptive) coping mechanisms rather than being due to inaccurate measurement.     

The influence of immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis

OBJECTIVES: In multiple sclerosis (MS), several neuroimmunomodulatory effectors are known, including melatonin. They are able to influence disease-related neurophysiogical changes (disability or impaired vision) as well as neuropsychological performance (e.g. cognition and depression). In this study we assessed the relationship between immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis. METHODS: We evaluated 26 young female patients with benign MS treated with/without immunomodulating therapies with regard to their physical disabilities (Expanded Disability Status Scale, EDSS), their visually evoked potentials (VEP), their plasma melatonin concentrations as well as their performance regarding emotional and cognitive tests and compared them with healthy matched controls. RESULTS: Patients with MS showed deficits in cognitive and emotional functions compared to healthy controls, which were in accordance with their increase in EDSS over time. However, in contrast to untreated patients, patients receiving immunotherapy showed significantly increased dysfunction with respect to actual mood (p = 0.02) and a tendency to increased depression scores (p = 0.072). However, neither treatment subgroup had cognitive deficits. In untreated patients, melatonin levels correlated with reduced scores in the cognitive tests (p = 0.045) but not with depression or VEP latencies. Patients with long-standing MS (>10 years) showed a significant correlation (p = 0.01) to their increased depression scores and their melatonin levels, but no correlation with VEP or cognitive dysfunction, compared to patients with shorter disease duration (< or =10 years). CONCLUSION: These results indicate that in MS all aspects of the psycho-neuroimmunological network can be affected. Despite the potential influence of immunomodulation on depression, no connection with melatonin representing the retinohypothalamic tract/pineal gland circuits could be detected. However, visual perception as well as visuoconstructive abilities were affected in MS patients. Neuropsychological tests in MS should concentrate on cognitive variables, which reflect the clinical status more accurately and may be used to monitor disease-modifying therapies.     

Goal attainment in cognitive rehabilitation in MS patients

The aim of the study was to investigate the predictive value of important disease-related variables on goal attainment in cognitive rehabilitation in multiple sclerosis (MS). The possible predictive value of executive functions, neurological disability, depression and general cognitive ability was assessed, employing Goal Attainment Scaling (GAS). Fifty-seven patients with MS were assessed for executive functions, neurological disability, depression and general cognitive ability, and guided through the process of formulating GAS-goals for coping with cognitive challenges in everyday life during a four week in-patient cognitive rehabilitation programme. GAS-goal attainment was scored during biweekly follow-up calls in the first three months post-discharge from the rehabilitation centre, and finally at seven months after the start of the rehabilitation. Consistent with the first study hypothesis MS patients succeeded in formulating and achieving GAS goals for coping with cognitive problems in everyday life. The patients were able to maintain a satisfactory level of goal attainment from the first measurement point after six weeks to seven months after the start of the rehabilitation. However, contrary to the second hypothesis, attainment of GAS goals was not predicted by executive functions. Neither was it predicted by neurological disability, depression or general cognitive ability. The findings suggest that GAS may be a practical and robust method in cognitive rehabilitation in MS patients, regardless of important disease-related characteristics.     

Neuropsychological deficits but not coping strategies are related to physical disability in multiple sclerosis

Detailed neuropsychological assessment was performed in 86 women (48 patients with stable relapsing-remitting multiple sclerosis (MS) and 38 matched healthy controls (HC)). Patients were categorized into patients without (EDSS < or =1, n = 26) and with physical disability (EDSS > or =2, n = 22). Patients with EDSS > or =2 scored significantly (P < 0.05) higher in Beck's depression inventory (BDI) and depression scores (DS) compared to HC and patients with EDSS < or =1. No significant differences were found with respect to the use of specific coping strategies between the patient groups, who preferred active (EDSS < or =1) or distracting (EDSS > or =2) strategies. Cognitive deficits were significantly increased in MS with EDSS > or =2 with regard to visuo-construction and visual memory, in particular with respect to geometric figures, compared to MS with EDSS < or =1. Significant positive correlations of depression variables (BDI, DS and BL) and depressive as well as denying coping strategies were found. Our results showed increased depression scores and increased cognitive deficits in advanced physically disabled patients, without selection of specific coping strategies. This supports an individual MS-specific neuropsychological therapeutic approach in order to improve disease related deficits together with social functioning.     

The role of anxiety level, coping styles, and cycle phase in menstrual distress

Using three samples, researchers investigated the relation between various anxiety levels, coping strategy use, and menstrual cycle phase to menstrual distress. In Studies 1 and 2, women low in anxiety sensitivity used more acceptance coping strategies and women high in anxiety sensitivity reported using more maladaptive coping strategies. In Study 2, women with medium anxiety sensitivity reported similar coping strategies to women low in anxiety. Menstrual cycle phase did not differentially affect coping strategy use in women varying in anxiety sensitivity levels in Studies 1 and 2. In addition to depressed mood emerging as a significant predictor of premenstrual distress in these two studies for all participants, avoidance coping for women high in anxiety sensitivity and problem-focused coping for women low in anxiety sensitivity were also significant predictors of premenstrual distress. In Study 3, during the premenstrual phase, women with panic disorder, compared to controls, reported using more avoidance coping whereas controls reported used more active coping and seeking social support for emotional and instrumental reasons. Results are discussed within a continuity model from high anxiety sensitivity to anxiety disorder for maladaptive coping and menstrual distress.     

Mood disorders in multiple sclerosis and the effects on cognition

BACKGROUND: Depression and cognitive dysfunction are common in patients with multiple sclerosis. However, it is unclear whether depression may cause or exacerbate cognitive problems as data remain equivocal. The current review attempts to clarify the relationship between these behavioral disorders. METHOD: The literature pertaining to the influence of depression on cognition in MS patients has been reviewed. RESULTS: Early studies consistently failed to find an association and concluded that cognitive dysfunction in MS patients occurred independently of depression. A more recent literature has found fault with this, citing numerous methodological flaws in the studies undertaken. Newer data now suggests that core symptoms of depression reduce cognitive capacity, in particular exerting an adverse effect on the executive function component of working memory. CONCLUSIONS: Depression may exacerbate cognitive dysfunction in MS patients. Whether treating depression will lead to cognitive improvement is not yet known, but warrants further exploration.     

Neuropsychological dysfunction, depression, physical disability, and coping processes in families with a parent affected by multiple sclerosis

BackgroundFamilies with a parent suffering from multiple sclerosis (MS) must cope with the unpredictable course of the disease. Most studies analyzing factors that influence coping abilities in families with a member affected with MS used questionnaires to assess this ability.MethodsOn the contrary, the present study used a semi-structured psychiatric interview and used the resulting information to calculate a general measure of coping ability (coping index [CI]). We administered this interview to 44 MS patients, their partners and offspring and conducted a neuropsychological and physical evaluation of the patients to determine the impact of physical disability, cognitive dysfunction, and depression on the process of coping by the patient, the healthy partner, and children.ResultsThe CI of patients was best predicted by measures of their depressive symptoms, divided attention, and estimated verbal intelligence. None of the patient variables predicted the CI of healthy partners or their offspring. We found an association between the CI of the healthy partner and the children.ConclusionsThese findings suggest that MS patients' emotional and neuropsychological functions are associated with their ability to cope with the disease. These should be carefully assessed at the beginning of treatment so that those factors known to negatively influence patient coping are targeted in the treatment plan if necessary. Comprehensive care of a patient with MS should include support of coping abilities of the family members.     

Sexual function and ways of coping in patients with multiple sclerosis and their partners

The sexual and marital life of people with multiple sclerosis (MS) and their partners is frequently affected by the disease. One hundred and sixteen MS sufferers (72 females, 44 males) and their partners were questioned about their sexual and marital satisfaction; specific sexual difficulties caused by MS; and ways of coping with sexual problems. Demographic data, impact and acceptance of MS, cognitive functioning and mood state were also measured. Results showed that both male and female patients had sex lives that were greatly affected by their disability. Problems included indirect physical changes (numbness, spasms and fatigue); direct sexual dysfunctions (impotence, vaginismus and anorgasmia); concerns about future changes (incontinence, fertility); and sexuality-related changes (priorities, expectations and communication with partner). Men had higher levels of sexual dysfunction and talked to their doctors more frequently compared with women. Three percent of women and 25% of men had been to a sexual therapist. Spouses also indicated high levels of sexual dysfunction, including the area of non-sensuality. Relationship difficulties were present in a third of the sample, with female partners being the most dissatisfied. Sexual dysfunction in patients was not associated with age, duration of illness or mood state. Partners' sexual dysfunction was associated with patients' age, duration of MS and illness impact.     

Pain and affective memory biases interact to predict depressive symptoms in multiple sclerosis

A large literature supports a direct relationship between pain and depressive symptoms among various patient populations. Patients with multiple sclerosis (MS) frequently experience both pain and depression. Despite this, no relationship between pain and depression has been found in MS. The present investigation explored the relationship between pain and depression in a sample of patients with MS. Consistent with cognitive theories of depression, results supported the hypothesis that pain would only contribute to depression when MS patients exhibited a concomitant cognitive vulnerability. Cognitive vulnerability to depression was measured using a performance based affective memory bias (AMB) task. Patients with high levels of pain and negative AMB reported more depressive symptoms compared to patients with pain and positive AMB. Implications for the identification and treatment of depression in MS are discussed.     

Investigating whether depressed youth exhibiting elevated C reactive protein perform worse on measures of executive functioning,verbal fluency and episodic memory in a large,population based sample of Dutch adolescents

Cognitive functioning is disrupted during a depressive episode and cognitive dysfunction persists when depression is in remission. A subtype of depressed individuals who exhibit elevated inflammatory biomarkers may be at particular risk for cognitive dysfunction. We examined whether an elevated inflammatory biomarker (C-reactive protein: CRP) in acute and/or remitted depression was associated with specific deficits in executive functioning, episodic memory, and verbal fluency. Data were drawn from a population-based sample of Dutch adolescents (N = 1066; 46% male) recruited at the age of 11 and followed over the course of eight years. We tested whether adolescents with either, (i) a history of depression (Wave 1–3) or (ii) current depression (Wave 4), and elevated levels of C-reactive protein measured in blood at Wave 3 performed worse on cognitive assessments at Wave 4. Eight measures of cognitive functioning were hypothesized to load on to one of three dimensions of cognitive functioning (executive functioning, episodic memory, and verbal fluency) within a structural equation model framework. Higher levels of CRP were associated with worse future executive functioning in adolescents with and without current/prior depression. A current depression diagnosis also was associated with worse executive functioning. There was consistent evidence linking low socioeconomic status and health-related covariates (high body mass index/sedentary behavior) with worse performance across multiple measures of cognitive functioning and, importantly, the association of depression/CRP and executive functioning was no longer significant when controlling for these covariates. Future studies may benefit from investigating whether specific depressogenic behaviors (e.g., sedentary behavior/substance use) mediate a relationship between depression and worse executive functioning, potentially via a prospective pathway through elevated inflammation.     

Possible interactive effects of demographic factors and stress coping mechanisms on depression and anxiety in maintenance hemodialysis patients

OBJECTIVE: The aim of this study was to assess the possible interactive effects of age, sex, duration of hemodialysis (HD), educational and income levels, and stress coping mechanisms on depression and anxiety in patients on maintenance HD. METHODS: Uremic patients (N=416), regularly undergoing HD for more than 1 year, who did not have apparent cerebrovascular disease or serious intellectual impairment, were investigated. The interactive effects of age, sex, duration of HD, and educational and income levels, in relation to stress coping mechanisms, on depression or anxiety were assessed by hierarchical multiple regression analyses. RESULTS: Regression lines illustrating significant (P<.05) interactions were constructed. The decrease in depression accompanying the increase in task-oriented stress coping was greater in highly educated patients than it was in the other patients. Anxiety levels decreased when patients had both high income and demonstrated a range of task-oriented stress coping mechanisms. For patients undergoing HD for long duration, or with a relatively high income, the decrease of depression and anxiety accompanying a decrease of emotion-oriented stress coping was greater, as compared with other patients. The decrease of depression accompanying an increase of avoidance-oriented stress coping was greater in patients with low income and in older patients than it was in the other patients. CONCLUSIONS: These findings may lead to the development of specific and focused interventions for depression or anxiety in maintenance HD patients.     

Coping behavior in depressed patients: a longitudinal study

The relationship of coping behavior to outcome in depressed patients was examined. Subjects (n=105) with major depressive disorder (n=85), depressive disorder not otherwise specified (n=7) or major depressive disorder with axis I comorbidity (n=13) were followed for 6 months. Their coping behavior (i.e. rumination, active distraction, cognitive distraction and dangerous activities) was defined using the Comprehensive Assessment List for Affective Disorders. Based on their Hamilton Rating Scale for Depression (HRSD) scores at 6 months, the patients were categorized as having had a good or a poor outcome. Severity of depression and coping behavior were similar among the three diagnostic groups. At baseline assessment, coping behavior was not correlated with either HRSD score or age. However, males were significantly more likely to be engaged in dangerous activity as a coping behavior than females. Patients with a good outcome at 6 months were significantly more likely to use rumination as a coping behavior while patients with a poor outcome were significantly more likely to use dangerous activity. Multiple regression analysis confirmed this finding, indicating that rumination and dangerous activity were significant predictors of outcome at 6 months. Rumination might be associated with good outcomes in depressed patients while dangerous activity might be associated with poor outcomes.     

Predictors of dyadic adjustment in multiple sclerosis

Because multiple sclerosis (MS) is usually diagnosed between the ages of 20 and 50, a time during which most people begin serious relationships, dyadic adjustment for MS patients is a salient issue. However, little is known about factors that might contribute to dyadic adjustment problems in MS. In the present study, we predicted that MS patients showing evidence of three common sequelae of MS--depression symptoms, fatigue and cognitive dysfunction--would be most likely to display problems with dyadic adjustment. Sixty-four MS patients and 49 significant others were assessed. Patient-reported dyadic adjustment was significantly (P at least <0.05) associated with depression (r = -0.48) and fatigue (r = -0.31), but not cognitive functioning. Significant other-reported dyadic adjustment was significantly associated with patients' depression (r = -0.38), fatigue (r = -0.30) and executive functioning impairments (r = 0.37). Stepwise regression analyses revealed that depression was the only significant predictor of dyadic adjustment, regardless of whether significant other (r2 change = 0.16) or patient-reported (r2 change = 0.22) dyadic adjustment was used as the criterion variable. If depression leads to dyadic problems in MS patients, treatment of depression may result in improved dyadic adjustment. Conversely, if dyadic problems contribute to depression in MS, then treatment of dyadic problems may lead to relief from depression in these patients.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews application of transcranial brain sonography (TCS) in MS patients and TCS findings related to neuropsychological dysfunction. TCS is a new neuroimaging method displaying tissue echogenicity of the brain through the intact skull. Whereas the cortex can not be discriminated from the subcortical white matter with TCS, subcortical brain structures such as ventricles and basal ganglia can be adequately displayed. Even though TCS proved sensitive and reliable in measuring widths of third and lateral ventricles in a number of neurodegenerative diseases, relatively few TCS studies on MS patients have been reported. Data of these studies suggest a good correlation of cognitive dysfunction and width of third ventricle which can be measured reliably with TCS. Moreover, abnormal TCS findings of basal ganglia were associated with cognitive impairment. However, TCS findings of midbrain structures, basal ganglia and ventricles did not correlate with fatigue or depression in MS patients. TCS has the advantages of low costs, short investigation times and unlimited repeatability. The use of third-ventricle and basalganglia TCS for predicting and monitoring neuropsychological impairment in MS patients, however, needs to be elucidated in further studies.     

Benign multiple sclerosis

A small fraction of patients with multiple sclerosis (MS) have a benign course of the disease. The definition of benign MS has been heavily weighted towards physical disability and in particular ambulation. However, patients who are fully ambulatory may still be heavily disabled by non-motor symptoms like fatigue, pain, depression and cognitive dysfunction. These non-motor symptoms should be considered when defining benign MS.     

Sonographic basal ganglia alterations are related to non-motor symptoms in multiple sclerosis

The anatomical basis of cognitive dysfunction and other non-motor symptoms in multiple sclerosis (MS) is poorly understood. In MS patients, transcranial sonography (TCS) shows neurodegenerative disease-like lesions of the substantia nigra (SN) and basal ganglia, thought to reflect iron accumulation. The present study deals with the question of whether sonographic changes of SN, brainstem raphe, lenticular nucleus (LN) or caudate nucleus are related to non-motor symptoms of MS. We used TCS to investigate 54 MS patients and 54 age- and sex-matched healthy subjects. Degree of cognitive (executive) dysfunction, fatigue, depression, and urinary urge incontinence in MS patients was assessed using the Paced Auditory Serial Addition Test, the Faces Symbol Test, the Modified Fatigue Impact Scale, the Beck Depression Inventory, and the Urinary Distress Inventory. Abnormal TCS findings of SN, brainstem raphe, LN, and caudate nucleus were found in 13, 7, 11, and 6% of the healthy subjects, but in 54, 43, 62, and 41% (each, p < 0.001) of the MS patients, with similar frequency in relapsing-remitting and primary or secondary progressive MS patients. Sonographic alteration of the LN correlated with cognitive dysfunction. Combined alteration of both, LN and SN, was clearly associated with cognitive dysfunction and cognitive fatigue. The combined sonographic alteration of SN and brainstem raphe indicated severe urinary urge incontinence irrespective of the presence of spinal MS lesions. No relation was found between depression and any of the TCS findings. These findings suggest that neurodegenerative processes affecting deep brain structures contribute to cognitive and autonomic dysfunction in MS.     

HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

The hypothalamus–pituitary–adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.