The neurobiological effects of work-related stress

Background
Recent national statistics evidence a continuous rise in the prevalence of stress. In the period from 2010 to 2021, the share of high scores on the stress scale rose from 20.8% to 29.1% in Denmark.1 Equally worrying trends are observed at international level, with more than 40% of the adults in a survey conducted in over 100 countries having felt stressed in the past few days.2 Work-related stress is a major contributor to the situation in both health and economic perspectives, causing massive burdens in lost earnings in our societies. Work-related stress often entails symptoms of decline in high-order functions and mood balance in patients, and yet little is known about how stress affects the human brain.

The NeuroWAD Project addresses the neurobiological effects of work-related stress in the human brain in a study population of stress patients who meet the requirements for inclusion in cognitive therapy at the Department of Occupational Health at Odense University Hospital, compared to healthy controls by Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), with the main focus on the properties of nuclear medicine. The project is based on an interdisciplinary framework including the fields of Occupational Health, Psychiatry, Neuroimaging and Genotyping, comparing stress patients to healthy controls. To obtain and combine data across these fields, the project developed through three main phases. 

Phase one
Here the project and original protocol were created (Paper I), as well as a systematic review of studies investigating the neurobiological effects of work-related stress with (PET) neuroimaging and the radiotracers 2-[ 18F]fluoro-2-deoxy-D-glucose (FDG) as an expression of neural activity and [ 11C]Raclopride as expression of binding potential of the neurotransmitter dopamine at receptor level was conducted (Paper II). 

Phase two
This phase was initiated with a series of static baseline (resting-state) scans of FDG uptake at voxel level in stress patients compared to healthy controls. This series also included COMT Val158Met polymorphism genotyping, which addresses genetically the possibility of predefined stress resilience related to dopamine (Paper III). The patients were screened in relation to psychosocial stressors in their work environment, mental health and confounding factors, according to clinical procedures. The mental health state of all participants was further assessed by means of Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interviews on the day of the brain scans. Secondly, phase two included a method study (Paper IV) designed to develop and test a novel functional FDG (fFDG) scan application for measuring relative changes in activation-task-evoked glucose consumption, at a single subject level, as accompanied by functional MRI imaging (fMRI). The study applied a motor task activation as an explorative proof of concept.  

Phase three
Base on the evolving explorative experimental setup, the last phase of the project combined and compiled the learnings from previous phases and the aims of the original protocol into a series of functional scans of seven stress patients and nine healthy controls. Here we developed a proof of concept paradigm for acquiring functional activation PET scans to explore higher order and affective functions of the human brain. The activation paradigm in phase three was based on the neuropsychological Stroop test. Each participant was subjected to two consecutive functional scans, applying the radiotracer (FDG) for assessing task-evoked activation of cerebral glucose uptake (fFDG) and the radiotracer [ 11C]Raclopride acting as a D2 dopamine receptor antagonist for evaluating dopamine-binding potential. Additionally in phase three, the data collection was supplemented with automation processing of the screening session, a Screen for Cognitive Impairment in Psychiatry (SCIP) and additional MRI acquisitions. 

Results
Phase one
Protocol article: “Neurobiological effects of work-related stress: Protocol for a case-control neuroimaging study”.
The systematic literature review found no relevant articles in the search of six databases.

Phase two
Stress patients showed significantly different scores in 18 key items out of 159 in the SCAN interview compared to the healthy controls, which in the NeuroWAD project serves as a measure of symptoms on the day of the scan. Static FDG scans indicated small clusters of decreased glucose consumption at resting-state in stress patients, primarily located in the white matter of frontal lobe sub-gyral areas. COMT detection indicated that stress patients are predominately present in both groups of homozygous alleles, whereas healthy controls were mainly located in the group of heterozygous allele. In the method study, the results showed an increase in the glucose metabolic rate, measured by fFDG in the peak region by 36.3-87.9% (mean 62.0%) during activation, on an intra-subject level, and regional spatial coincidence visually compared to the fMRI BOLD result, however with moderate discrepancy at more detailed levels.  

Phase three
Phase three compiled learnings from the previous phases into a single research paradigm, including automated recruitment and work-environment screening, psychiatric interviews, SCIP cognitive testing, performance log of in-scanner Stroop-test activation, measured by means of functional brain PET-scans with both FDG and Raclopride, fMRI and an extensive assortment of additional MRI sequences. Data collection has been completed and includes more than 300 unique datasets from the seven stress patients and nine healthy controls, interrelated across the interdisciplinary fields of the NeuroWAD Project. Data analysis has not yet commenced. 

Conclusion
The aim of the NeuroWAD Project was to provide an interdisciplinary investigation of the neurobiological effects of work-related stress on the human brain, giving rise to a well-defined and running experimental pipeline. This has at present time resulted in four articles illustrating the complexity of bridging psychosocial work environment, aspects of genetics and the advanced principles of PET/MRI neuroimaging. 

Based on the initial screening of stress patients, we learned that the progress of the stress condition is multifactorial, and our understanding of the ethology and of our participants would benefit from further investigations. Likewise, the development of the novel functional PET scan applications for measuring task-evoked changes in neural activity in the brain at a single-subject level is an entirely new advancement in the investigation of the physiology of brain functions, lifting the abstraction and information level beyond static PET and fMRI scans.