Short summary

Today, stress is one of the greatest disease burdens and causes of lost earnings on the labor market. This is a tendency that applies throughout the Western world, where mental health and brain power has increasingly becoming the most valuable and important ressource of the future.

Based on the symptoms that stress-patients report in relation to cognitive and emotional functions, i.e. problems with attention and concentration, as well as depressed mood, this project aims to investiga

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Rationale

The main objectives of this study are:

1) To investigate the association between work-related adjustment disorder in patients' exposure to stressors in the psychosocial work environment and the possible effects on the human brain, with special reference to the dopaminergic pathways forming basis of reward processing and executive functions in the human brain.

2) To develop a data management methodology for establishing an independent research area within the field: Neurobiology of Occupational Medicine and Psychology. 

The aim is to establish an interdisciplinary case-control research study, focusing on the influence of modern work-life stressors on the human brain in patients with adjustment disorder due to stressors in the psychosocial work environment and an age and gender matched control group.

Dopamine (DA) appears to be crucial in many of the abilities we consider important in modern work tasks, such as learning, planning, problem solving and motivation. This project is based on the hypothesis that it is possible to detect changes in the brain's DA-based mesocorticolimbic projections in patients diagnosed with a work related adjustment disorder. The changes will manifest in altered glucose metabolism in relation to neural activity and altered DA radiotracer binding potential at neurotransmitter and receptor level, referring to the density of available D2 receptors and the affinity of the respective radiotracer.  The project combines disciplines of Neurobiology, Psychiatry, Psychology and Occupational Health.   

Research objectives

This project is conducted as a PhD project and consists of 4 subprojects, i.e. a systematic review and three positron emission tomography (PET) studies each with a specific PET tracer.

1. Systematic literature review: Overview of studies and results in the interdisciplinary field of neu-robiology, PET imaging, and occupational medicine and psychology.  
2. FDG investigation: Comparison of cerebral glucose metabolism globally and regionally in the pre-frontal cortical system and the striatum.
3. [11C]raclopride investigation: Comparison of the dopaminergic binding potential in the ventral striatum/nucleus accumbens. 
4. [11C] FLB 457 investigation: Comparison of dopaminergic binding potential the extrastriatal do-paminergic pathway of the prefrontal cortex. 

The project is based on empirical observations that indicate that a loss of motivation, comparable to the symptoms of anhedonia and apathy, can be a preceding symptom for later work related adjustment disorder. This loss of motivation is believed to occur on an earlier onset than the physiological symptoms and reactions to stress, depression and anxiety.

Social aspects

Mental disorders pose one of the greatest challenges to modern societies to day. These disorders are the costliest diseases in Denmark and the major cause of lost earning in the Danish corporate sector. Their prevalence is increasing in all Western countries. The countries with the highest prevalence also tend to have the highest rates of occupational frequency, i.e. the highest number of working hours distributed by gender in the 16-64 age span. Danish and international scientific studies clearly show that there is a significant correlation between psychosocial stressors in the work environment and the development of mental disorders, also increasing the risk of dementia, cardiovascular disease, and accidents. National and international studies detail the aetiology behind work-induced mental disorders and the prevailing stressors that cause these conditions, with the most pertinent factors being: job security, influence on work situation, support form management and colleagues. There is a noticeable lack of scientific studies seeking to elucidate whether there is a link between psychosocial work stressors and brain metabolism and signal transmission.

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Description of the cohort

The department of Occupational and Environmental Medicine (DOE) at OUH will recruit patients both diagnosed according to the ICD10 F43.2x and exposed to predominant psychosocial work stressors. Based on the diagnosis and evaluations the DOE selects the relevant patients. At the first visit to the DOE immediately after the diagnostic interview the, patients will presented to the option of participating in this project, by qualified personnel who have been instructed by the main investigator. At this point, the main purpose and procedures of the investigation will be presented orally and written information is supplied for the patients to take home. Shortly after, one or two days, these patients will be contacted by phone by a member of staff from the DOE or the main investigator. In this conversation the patients will be presented to the details of the project as well as an evaluation regarding the suitability to participate concerning the restrictions connected to PET-scanning. If interested, the patient will be invited to a personal meeting at Odense University Hospital, with the possibility of bringing an assessor. Due to the nature of neurobiology, the scans must be conducted within a fairly short time period after the initial diagnosis. Hence declaration of consent will be presented and signed at the day of the first scan, also ensuring that all additional questions can be answered by the main investigator. The scans will be conducted within a fortnight after the first contact.

Recruitment criteria: The patients are recruited among women aged 34-54 years with an educational level corresponding to a bachelor, as these subjects represent the largest affected group in the Danish workforce. At the DOE subjects undergo a clinical diagnostic interview based on the ICD 10 criteria including screening for stressors in the psychosocial work environment and their relationship to disease development, private life strains, personal background, mental vulnerability, and competing somatic disease, as well as tests for depression and anxiety symptoms, respectively the Beck Anxiety Inventory (BAI) and Major Depression Inventory (MDI). The psychosocial work environment stressors being screened for are: quantitative demands, emotional demands, role conflict, role ambiguity, support and encouragement, organizational justice, adequate education and training (skill level). The experience of stressors is assessed in relation to the most dominant stress models, "demand-control-support" (Karasek), "effort and reward imbalance at work" (Siegrist), "Stress as Offense two self" (Semmer), and classical stress theory focusing on appraisal/coping (Lazarus or Ursin). The DEO evaluates approximately 30 suitable subjects a month and estimate 20% accept of participating in this project. Inclusion and exclusion criteria are described in the appendix, which also holds details about the PET/MR studies. In connection with the scans, the main investigator will conduct an SCAN-PSE interview for the assessment of mental symptoms to determine if the participant's condition has changed since they decided to participate in the trial. Healthy controls are recruited at OUH Blood Bank and matched with regard to gender, age, educational and occupational background. Further, they are screened for confounding factors in a similar manner as the patient group.

Data and biological material

By means of PET/MRI and selected PET tracers, we will be able to investigate not only structural conditions with MR but the metabolic activity in specific brain regions, and the neurobiological DA and D2 receptor composition and possible changes in the mesocorticolimbic projection, cf. descriptions of subprojects 2-4 below. With the new generation PET/MR scanner, which is available in Odense in the autumn of 2017, we will acquire combined functional and morphological information of unprecedented quality using such a low level of radiation (same magnitude as the background radiation) that later follow up studies are possible. The PET/MRI studies are observational case-control studies to identify factors in F43.2 patients that may cause a pathological cerebral condition, which is not identifiable in comparable, healthy control subjects.

• 1) Radiotracer [18F]FDG study

[18F]fluorodeoxyglucose (FDG) PET is the primary imaging modality we apply to measure glucose metabolism in the brain, as this is tightly connected to neural activity. We want to examine whether symptoms of cognitive and motivational/reward deficits are attributable to frontal lobe and striatal changes in glucose metabolism in F43.2 patients compared to a control group. Due to the lack of unified scientific literature, this sub-project constitutes an indexing basis for the overall project hypothesis. Initially we wish to investigate global glucose consumption in patients versus controls. In addition, we investigate regional differences in glucose metabolism in the Striatum in connection to the reward circuitry of the mesolimbic DA projection. Finally, the prefrontal, dorsolateral prefrontal, and anterior cingulate cortex are addressed as these regions of interest (ROIs) are known to be strongly involved in the executive circuit of working memory and attention, including that DA influences performance in working memory tasks.

During scans, the participants will perform a neuropsychological reward and an executive task. Numerous neuropsychological test batteries are available. A well-established test in PET studies regarding reward is the "Monetary Reward Task", and in relation to executive functions the "Stroop" are among the most often applied tests. If possible, the same participant will be enrolled in both the reward related session and the session addressing executive functions. Apart from investigation of baseline conditions, these tests also allow us to study the neurobiological function related activity during performance. In addition, they provide data to evaluate if patients on average actually show deficits in performing compared to control subjects.  

PET procedures:

• The PET procedures follow existing protocols at the Dept. of Nuclear Medicine, OUH, which performs about 50 PET/CT procedures on work days. This study uses modifications enabled by a new generation of solid state high sensitivity detectors already in use in two new generation PET/CT devices (GEHC Discovery MI) running in the department taking into account specific advantages of the GEHC Signa PET/MR scanner which will be installed and running during the autumn 2017.  Special protocols for all three types of study are being elaborated.
• All patients will be examined with all three tracers, the timing of which depends on the avail-ability of the three tracers in relation to pending changes of the radiochemical production schedules in relation to the installation of cyclotron #2 at the OUH facility.  
• Baseline acquisition is made in all patients and control subjects. An additional imaging session follows in all subject after complete decay of the first injection's tracer, depending the tracer halflives. The second imaging session happens in connection with reward task or executive task performed for the measurement of task-induced-activation.

The hypothesis of this sub-project is that it will be possible to detect altered glucose uptake in the regions of the prefrontal cortex and the striatum corresponding to the basis of executive and reward functions of the brain in patients compared to controls.

• 2) Radiotracer [11C]raclopride study

Based on the results of the FDG-study the pathological analysis of possible changes in the brain's reward system in a DA context is performed as a PET investigation by the means of the radiotracer 11C-raclopride, which is the most validated tracer to address the binding potential of D2 receptors in the Striatum. Raclopride acts as a selective antagonist at D2 DA receptors and the method is extremely sensitive, so that only a few nanograms of the tracer are needed. Therefore, participants will receive a minimal radiation dose during scanning. Moreover, the tracer 11C decays rapidly (T½ = 20 min). During the scan participants will perform the same neuropsychological reward test as in the FDG-study.

• 3) Radiotracer [11C]FLB 457 study

Cognitive deficits and reduced abilities in performing executive functions are believed to be related to changes as a consequence of possibly impaired mesocortical dopaminergic transmission in the extrastriatial regions of the prefrontal cortex. [11C] FLB 457 is a radiotracer with greater affinity for D2 receptors than that of raclopride and is considered the most suitable radiotracer to address the cortical DA projection. The main ROIs in this investigation are constituted of the dorsolateral prefrontal cortex (DLPFC), orbital frontal cortex (OFC), medial prefrontal cortex (MPFC), and anterior cingulate cortex (ACC). Procedures are similar to those of the FDG-study. 

Collaborating researchers and departments

Dept. of Clinical Physiology and Nuclear Medicine, University Hospital Rigshospitalet

• Thomas Lund Andersen

Center for Neuropsychiatric Depression (CNDR), Mental Health Center Glostrup, University of Copenhagen

• Poul Videbech

Department of Occupational and Environmental Medicines (DOE), Odense University Hospital

• Lars Brandt

Department of Nuclear Medicine, Odense University Hospital

• Oke Gerke
• Svend Hvidsten

Publications associated with the project

Madsen SS, Gjedde A, Brandt L, Pihl-Thingvad J, Videbech P, Gerke O, Højlund-Carlsen PF. Neurobiological effects of work-related stress: protocol for a case-control neuroimaging study. Dan Med J. 2018 Nov;65(11):A5513. PMID: 30382017.

Madsen SS, Naghavi-Behzad M, Piri R, Gerke O. FDG/Raclopride-PET neuroimaging in work-related stress - A systematic review. Eur Neuropsychopharmacol. 2023 May;70:29-31. doi: 10.1016/j.euroneuro.2023.02.013.

Madsen SS, Hvidsten S, Andersen TL. Functional FDG-PET: Measurement of Task Related Neural Activity in Humans-A Compartment Model Approach and Comparison to fMRI. Diagnostics (Basel). 2023 Oct 4;13(19):3121. doi: 10.3390/diagnostics13193121.