The brain is the central organ for adaptation to different stressors and is responsible for altering systemic functions through neuroendocrine, autonomic, immune and metabolic systems. The adaptive stress response mechanisms can be defined on different methodological levels, including determination of neurometabolite contents, assessment of stress hormones, and analysis of epigenetic mechanisms. Knowledge of the neurometabolic alterations underlying the brain’s response to stress in healthy humans may help to understand the mechanisms of adaptive stress responses, and provide reference for distinguish maladaptive responses.
Different models have been used to explore how the human brain responds to acute stress. Psychological models, such as the Trier Social Stress Test, were used to induce acute stress; however, the inter-individual response is highly variable and depends on factors such as motivational factors, personality traits and underlying emotional regulation capabilities.1 Exercise can be used to induce stress; however, factors such as physical fitness and motivational factors determine individually the amount of stress associated with exercise training.2 The glucose clamp technique was used to examine the differential response of brain and muscle to hyper- and hypoglycemic stress. An increase of brain ATP was demonstrated, suggesting that the brain can activate specific mechanisms to modulate energy status during variations in glucose supply in contrast to peripheral organs.3 However, this technique has several side effects and limitations such as hypoglycemia-induced arrhythmia, making the method less feasible for the use in healthy volunteers and patients.4
Fasting induces psychological and metabolic stress by decreasing the amount of energy available to the organism. Several reports have shown that fasting is associated with fluctuations in mood and cognition, in particular depressed mood and difficulties in concentration.5,6 On a metabolic level, fasting is associated with weight loss, and an increase in hypothalamus–pituitary–adrenal system activity with subsequent hypercortisolism.7,8 Some of the above-mentioned alterations have also been observed in psychiatric disorders, such as major depressive disorder (MDD). MDD is characterized by a depressed mood that is typically accompanied by weight loss and alterations in cognition and appetite.9,10 On an endocrine level, upregulation of the hypothalamus–pituitary–adrenal axis with subsequent hypercortisolism has frequently been observed.11 Interestingly, neurometabolic alterations have also been reported in MDD. These findings comprise a decrease in central glucose utilization,12 being more prominent in patients with severe depression and in patients with suicide attempts,13,14 increased Cho/Cr levels in the basal ganglia, and decreased Glx levels.15 Given these similarities, it is of interest to examine whether healthy subjects without depression may have different neurometabolic responses. Fasting may also act as a stimulation paradigm to examine the compensatory response to acute energetic stress. Fasting can be standardized and is independent from underlying motivational factors and personality traits. It can be applied to healthy volunteers or different patient populations, making the method feasible for comparisons of the stress response in healthy and pathological states. Fasting for up to three days has reliably been shown to induce stress hormone alterations including hypercortisolism, which is common to several stress models and points to brain adaptive response to energetic stress.7,8
Proton magnetic resonance spectroscopy (1H-MRS) can be used to study brain metabolism in vivo by detecting cerebral metabolites such as N-acetyl-aspartate (NAA), total creatine (tCr), total choline (tCho), the mixture (Glx) of glutamine (Gln) and glutamate (Glu), and myo-inositol (mI).16 While conventional 1H-MRS techniques are suitable only for studies carried out on a small brain region,17 thus limiting potential applications, a recently established whole brain MR spectroscopic imaging (wbMRSI) can map metabolites over large fractions of the brain.18 Thus, the wbMRSI offers a new method to gain information on the biochemical processes underlying normal brain function and pathological states,19,20 and provides a powerful tool to explore metabolic response of the brain to standardized stressors, such as fasting stress.
This FAST*BRAIN study has been designed to examine the adaptive stress response to 72 h of complete food deprivation in healthy volunteers and in pathological conditions, with neurometabolic responses in human brain being studied by using the wbMRSI technique. Here we present the results obtained from 15 healthy women to demonstrate the feasibility of the study and to yield reference data for patient studies.