Simone Kern

Glucose metabolic changes in the prefrontal cortex are associated with HPA axis response to a psychosocial stressor

The prefrontal cortex (PFC) has been well known for its role in higher order cognition, affect regulation and social reasoning. Although the precise underpinnings have not been sufficiently described, increasing evidence also supports a prefrontal involvement in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. Here we investigate the PFCs role in HPA axis regulation during a psychosocial stress exposure in 14 healthy humans. Regional brain metabolism was assessed using positron emission tomography (PET) and injection of fluoro-18-deoxyglucose (FDG). Depending on the exact location within the PFC, increased glucose metabolic rate was associated with lower or higher salivary cortisol concentration in response to a psychosocial stress condition. Metabolic glucose rate in the rostral medial PFC (mPFC) (Brodman area (BA) 9 and BA 10) was negatively associated with stress-induced salivary cortisol increases. Furthermore, metabolic glucose rate in these regions was inversely coupled with changes in glucose metabolic rate in other areas, known to be involved in HPA axis regulation such as the amygdala/hippocampal region. In contrast, metabolic glucose rate in areas more lateral to the mPFC was positively associated with saliva cortisol. Subjective ratings on task stressfulness, task controllability and self-reported dispositional mood states also showed positive and negative associations with the glucose metabolic rate in prefrontal regions. These findings suggest that in humans, the PFC is activated in response to psychosocial stress and distinct prefrontal metabolic glucose patterns are linked to endocrine stress measures as well as subjective ratings on task stressfulness, controllability as well as dispositional mood states.

Psychoneuroimmunology - Cross-talk between the immune and nervous systems

Psychoneuroimmunology is a relatively new field of study that investigates interactions between behaviour and the immune system, mediated by the endocrine and nervous systems. The immune and central nervous system (CNS) maintain extensive communication. On the one hand, the brain modulates the immune system by hardwiring sympathetic and parasympathetic nerves (autonomic nervous system) to lymphoid organs. On the other hand, neuroendocrine hormones such as corticotrophin-releasing hormone or substance P regulate cytokine balance. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and immune system-mediated disease.

Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis vulgaris)—do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)?

In previous research we reported attenuated responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis and further, an increased reactivity of the sympathetic adrenomedullary (SAM) system to stress in patients suffering from atopic dermatitis (AD). AD is a chronic inflammatory skin disease mainly triggered by TH(2)-dependent inflammatory processes. The specific goal of the present study was to investigate whether altered HPA axis and SAM system responsiveness to stress can also be found in TH(1)-mediated inflammatory conditions. Patients with psoriasis (PSO; n=23), a TH(1)-mediated inflammatory (autoimmune) skin disease and healthy controls (n=25) were exposed to a standardized laboratory stressor (TSST) which mainly consists of a free speech and a mental arithmetic task in front of an audience. To investigate HPA axis and SAM system responsiveness, cortisol, ACTH, and catecholamines were determined before and after the stress test. In addition, cortisol levels after awakening and cortisol levels during the day (short diurnal profile) were determined. In order to test feedback sensitivity of the HPA axis, a dexamethasone (DEX) suppression test (0.5 mg) was performed. Analysis of cortisol and ACTH levels after the stress test yielded no significant differences between PSO subjects and controls indicating no altered HPA axis function in this patient group. Further, no between-group differences were found in cortisol levels after awakening or during the day (short diurnal profile). Additionally, no difference between PSO and healthy subjects in the feedback sensitivity of the system could be found (DEX test). However, PSO patients showed elevated epinephrine (F(3,102)=4.7; p<0.005) and norepinephrine (F(3,135)=2.7; p<0.05) levels in response to the stress test when compared to the controls. These findings suggest no altered HPA axis responsiveness, but increased reactivity of the SAM system in TH(1)-mediated chronic inflammatory skin disease.

Effects of glatiramer acetate on fatigue and days of absence from work in first-time treated relapsing-remitting multiple sclerosis.

ObjectivesTreatment of multiple sclerosis patients with glatiramer acetate has been demonstrated a beneficial effect on disease activity. The objective of this prospective naturalistic study was to evaluate the impact of glatiramer acetate on fatigue and work absenteeism.Methods291 treatment-naïve patients with relapsing remitting multiple sclerosis were included and treated with glatiramer acetate for twelve months. Relapse rates, disability, fatigue symptoms, days of absence from work and adverse events were monitored. Fatigue was measured with the MFIS scale and with a visual analogue scale.ResultsTotal MFIS scores decreased by 7.6 ± 16.4 from 34.6 to 27.0 (p ≤ 0.001). Significant reductions were observed on all three subscales of the MFIS. Fatigue symptoms, assessed using a visual analogue scale, decreased by 1.04 ± 2.88 cm from 4.47 cm to 3.43 cm (p ≤ 0.001). The proportion of patients absent from work at least once was reduced by a factor of two from 65.1% to 30.1% (p ≤ 0.001). Tolerance to treatment was rated as very good or good in 78.3% of patients. Adverse effects, most frequently local injection site reactions, were reported in 15.1% of patients.ConclusionTreatment with glatiramer acetate was associated with a significant improvement in fatigue symptoms and a marked reduction in absence from work. Treatment was well-tolerated. Such benefits are of relevance to overall patient well-being.

Employment status in multiple sclerosis: impact of disease-specific and non-disease-specific factors.

Background: Multiple sclerosis (MS) is associated with high rates of early retirement (ER). Objectives: A German cohort of MS patients and healthy control subjects (HCs) were compared cross-sectionally to investigate disease- and non-disease-specific factors that are associated with employment status (ES) in MS and to identify predictors of ES in MS. Methods: A total of 39 ER MS patients, 48 employed MS patients, and 37 HCs completed a brief neuropsychological battery and questionnaires related to depressive symptoms, fatigue, health-related quality of life (HrQoL) and health locus of control (HLC). Neurological disability was assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). Results: ER compared with employed MS patients scored significantly higher in neurological disability, depressive symptoms and fatigue and significantly lower in cognitive functioning and HrQoL. Further, both groups differed with regard to age, education, disease course and duration but not in HLC. Neurological disability, age and fatigue were identified as significant predictors of ES in MS. Conclusions: ES in MS was associated with demographic aspects, neurological and cognitive status, depressive symptoms, fatigue and HrQoL but was not associated with HLC. Findings confirm neurological disability, age and fatigue as independent predictors of ES in MS.

Evidence-based patient information programme in early multiple sclerosis: a randomised controlled trial

Objective To evaluate the efficacy of an evidence-based patient information programme aiming to increase informed choice in patients with early multiple sclerosis (MS). Background Patients with early MS face a number of uncertainties concerning diagnosis, prognosis and effectiveness of immunotherapy. Prior studies suggest that evidence-based patient information combined with group education can promote informed choice in MS patients. Methods A 12-month, six-centre, double-blind randomised controlled clinical trial with 192 patients with a diagnosis of confirmed relapsing-remitting MS or clinical isolated syndrome in Germany. A 4-h interactive evidence-based educational programme was compared with a 4-h MS-specific stress management programme. The primary endpoint was informed choice after 6 months comprising risk knowledge and congruency between attitude towards immunotherapy and actual immunotherapy uptake. Secondary endpoints included autonomy preference, decision autonomy, decisional conflict and satisfaction, anxiety and depression, and number of immunotherapies. Results For the primary endpoint, a significant difference was shown with 50 of 85 (59%) participants in the intervention group achieving informed choice after 6 months compared with 18 of 89 (20%) in the control group (OR 0.2 (95% CI 0.1 to 0.4), p<0.001). Four weeks after the intervention, more participants in the intervention group showed good risk knowledge (difference between groups 39% (95% CI 26% to 53%), p<0.001). There were no significant differences between groups for attitude towards immunotherapy and for immunotherapy uptake. There were trends towards increased autonomy preference after the intervention and increased adherence to immunotherapies in the intervention group. Conclusions The intervention significantly increased informed choice and relevant risk knowledge without negative side effects.

Neurological disability, psychological distress, and health-related quality of life in MS patients within the first three years after diagnosis.

Background Psychological distress and psychiatric co-morbidity are common in multiple sclerosis (MS) and is often associated with neurological disability as well as reduced quality of life. Objectives This study aimed to investigate psychological distress and the possible association with quality of life as well as neurological disability in MS patients within the first 3 years after diagnosis. Methods Psychological distress was measured using a standardized questionnaire (Symptom-Check-List-90-R; SCL-90-R) in 31 relapsing–remitting MS patients and 24 sex- and age-matched healthy controls. Results Psychological distress was significantly more pronounced in MS patients when compared to healthy controls. Interpersonal sensitivity and psychoticism were positively associated with neurological disability (Expanded Disability Status Scale [EDSS]). A high EDSS group (median split EDSS; 1.5) expressed significantly more psychological distress when compared to the low EDSS group and healthy controls. MS patients with minimal to no neurological disability (low EDSS group) also expressed significantly more emotional distress when compared to healthy controls. MS-related quality of life was positively associated with neurological disability as well as SCL-90-R scores. After adjusting for neurological disability, psychological distress was still significantly associated with quality of life. Conclusions Early stage MS patients significantly differ in their psychological distress when compared to healthy controls. Psychological distress in these patients is associated with neurological disability, but it is also present in patients with minimal to no neurological disability. Psychological distress was identified as an independent predictor for MS-related quality of life.

Brain-immune communication psychoneuroimmunology of multiple sclerosis

The central nervous system (CNS) and the immune system are two extremely complex and highly adaptive systems. In the face of a real or anticipated threat, be it physical (eg, infection) or psychological (eg, psychosocial stress) in nature, the two systems act in concert to provide optimal adaptation to the demanding internal or environmental conditions. During instances of well being, the communication between these two systems is well tuned and balanced. However, a disturbed crosstalk between the CNS and the immune system is thought to play a major role in a wide series of disorders characterized by a hyporesponsive or hyperresponsive immune system. In multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease, an excess of inflammatory processes seems to be a hallmark and there is growing evidence for a disturbed communication between the CNS and the immune system as a crucial pathogenic factor. While the exact mechanisms for these phenomena are still poorly understood, the young discipline of psychoneuroimmunology (PNI), which focuses on the mechanism underlying the brain to immune crosstalk, might offer some insights into the existing pathogenic mechanisms. Findings from the field of PNI might also help to gain a better understanding regarding the origin and course of MS clinical symptoms such as fatigue and depression.

Personality characteristics in chronic and non-chronic allergic conditions

In psycho-allergological research, the potential relevance of personality factors in the maintenance and exacerbation of atopic symptoms is still a matter of debate. The present study aimed to assess personality dimensions in chronic atopic disease, i.e. atopic dermatitis (AD) and in acute manifestation of atopy (seasonal allergic rhinitis, SAR). Further, the association of a potentially atopy-specific personality profile with atopy-relevant biological stress responses should be evaluated. Subjects suffering from AD (n=36), or SAR (n=20) and non-atopic controls (n=37) were investigated. To determine different personality domains, Spielbergers State-Trait Anxiety Inventory (STAI), the Questionnaire for Competence and Control (FKK) and the Questionnaire for Stress Vulnerability (MESA) were administered. To assess the relation between these personality dimensions and biological stress responses, atopics and non-atopic controls were exposed to a standardized laboratory stressor (Trier Social Stress Test, TSST). Endocrine (cortisol, ACTH), immune (total IgE, leukocyte subsets) and physiological (heart rates) measures were recorded before and after the stress test. When compared to healthy controls, AD and SAR patients showed significantly higher trait anxiety (STAI) and stress vulnerability in situations characterized by failure, job overload and social conflicts (MESA). Moreover, AD subjects scored significantly lower in self-competence and self-efficacy (FKK) as well as in recreation ability (MESA). No difference trait anxiety and stress vulnerability could be detected between AD and SAR subjects. Pearson correlational analyses yielded no significant correlation between the different personality domains and the endocrine, physiological and immunological stress responses. However, stress-induced increase in eosinophil number was significantly correlated with the perceived self-competence/self-efficacy in SAR patients.

Cortisol Awakening Response Is Linked to Disease Course and Progression in Multiple Sclerosis

Objectives Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited. Methods A total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures. Results RRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R2 = 67%) for RRMS patients. Conclusions Circadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.