Effect of Metabolic State on Anxiety in Human Subjects

Overview

In this study, we would like to explore the hypothesis that changes in metabolic state, induced by altering hormone levels and patterns of neural activity, affect the experience of anxiety in humans. We will also investigate if there is a link between high anxiety and higher caloric intake. Our aim is to characterize whether changes in current metabolic state systematically influence anxiety induced by a well established behavioral task known as the threat of shock. The neural regions activated by this behavioral task in healthy subjects have been well characterized. We have a priori regions of interest that include the insula, anterior cingulate cortex, hypothalamus, amygdala, and prefrontal cortex. As our primary outcome, we will assess neural activation with whole-brain functional magnetic resonance imaging to determine whether brain regions are differentially engaged when subjects experience anxiety across different metabolic states. We will correlate these changes with psychophysiological measures of anxiety and metabolic state.

There is evidence that our subjective experience of the world is strongly influenced by our metabolic state, the status of our body's energy reserves and level of hunger. Hormones that regulate appetite, food ingestion and body weight apparently also exert their action on neuroanatomical circuits involved in the generation of psychological states. Previous research indicates that an individual's metabolic state may influence their susceptibility to and experience of anxiety. Conversely, stress can also modulate appetite and body weight regulation. There are many clinical implications of the bidirectional relationship between stress/anxiety and metabolic state/energy regulation but two of the most important ones are obesity and eating disorders. In terms of obesity, the high recidivism after successful weight loss underscores the limited use of caloric restriction to treat obesity. It is unknown whether dieting (fasting) increases anxiety, which eventually may undermine an individual's motivation to restrict food intake. Research shows that anxiety can increase appetite and exacerbate the physical and psychological manifestations associated with hunger. However, there is a paucity of experimental data establishing whether the metabolic changes associated with fasting influence the experience of stress and possibly, an individual's ability to continue dieting for an extended period of time. In the setting of both obesity and anorexia nervosa, the levels of metabolic hormones are different to those found in people of normal body weight. It is therefore likely that the activation of brain regions associated with energy and body weight regulation is abnormal. Many of these brain regions are also involved in the control of anxiety responses. The fact that there is a high comorbidity between anorexia nervosa and anxiety disorders indicates the potential contribution of metabolic states to the perception of stress. To better understand the relationship between metabolic state and anxiety, we will examine whether changes in metabolic state influence anxiety in human subjects. We will use whole-brain functional magnetic resonance imaging (fMRI) to identify the neural mechanisms that underlie metabolic state-dependent changes in the response to anxiety-inducing stress. In a randomized crossover design, participants will be tested in a well-established behavioral task that elicits anticipatory anxiety in two separate sessions that differ with respect to their metabolic states. We aim to perform a fine-grain analysis of changes in neural and physiological responses to this anxiety-inducing task as a function of metabolic state. Using fMRI as well as non-invasive psychophysiological measures, we will characterize whether there are systematic differences in the neural and psychophysiological experience of anxiety across different metabolic states in obese as compared to lean individuals.