Effect of Metabolic State on Anxiety in Human Subjects
Effect of Metabolic State on Anxiety in Human Subjects
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.
Inclusion Criteria:

 -  Men and women aged 20 - 40 years.

 -  Body Mass Index (BMI) from 19.0 to 25.0 for the lean population or Body Mass Index
 (BMI) equal to or greater than 30 for the obese population and under 300lbs
 (136.07kg.)

 -  Fluent in English

 -  Females must report a normal menstrual cycle length defined as from 24-35 days, with a
 period lasting from 2-7 days

 -  Stable weight (+/- 5 %) for at least three months prior to each admission and under
 300 lbs (136.07kg.)

 Exclusion Criteria:

 -  Weight of > 300 lbs (136.07kg.)

 -  Patients may not have had > 550 mL of blood drawn within 8 weeks of study entry.

 -  Less than 8 weeks after receiving an investigational new drug (IND). Patients must
 have a minimum of an 8 week washout period.

 -  Left-handedness.

 -  Any employee of Rockefeller University who knows the details of this study

 -  Reported history of claustrophobia.

 -  Reported history of metal implants, pacemaker, IUD, braces, or tattoos less then 6
 months old.

 -  Reported history of smoking, chewing tobacco or use of nicotine patches within the
 previous 3 months.

 -  Reported history of alcohol abuse/dependence.

 -  Reported use of prescription medication for pain, anxiety or sleep more than once a
 week.

 -  Reported daily ingestion of herbal (including melatonin) or dietary supplements within
 one month prior to the screening.

 -  Reported use of medications or herbal supplements that affect appetite or body weight
 within the previous three months.

 -  Reported history of using the following medications: glucocorticoids, anti-seizure
 medications, thyroid hormones in the past six months.

 -  Reported Psychiatric disorder requiring medication or treatment.

 -  Reported history of cardiac disease.

 -  Reported history of illnesses that affect metabolic hormone levels: renal or hepatic
 failure, type 1 or type 2 diabetes, lymphoma, hypogonadism,
 malabsorption/malnourishment, hypo- or hyper-thyroidism, hypercortisolism or any
 endocrinopathies.

 -  Reported history of physical exercise >2 hours per day.

 -  Reported history by female subjects of amenorrhea (no periods for longer than 3 months
 (even with negative uhCG) and oligomenorrhea (length greater than 35 days.)

 -  Pregnant (verified by urine hCG) or breast-feeding within the past 3 months.

 -  Eating disorder as suggested by at least 2 'yes' answers on the SCOFF Eating Disorder
 Questionnaire.

 -  Alcohol dependence as suggested by at least 2 'yes' answers on the CAGE Questionnaire.

 -  Current use of any illicit drug (including "recreational use") as verified by urine
 toxicology test.

 -  Anemia defined as Hgb < 12g/dL for male subjects < 11g/d/L for female subjects.

 -  TSH level that is outside the reference range of 0.3 - 0.5 mU/L or free T4 level that
 is outside the reference range of 4.5 - 11.2 mcg/dL (performed only if an abnormal
 thyroid gland identified on physical examination.)

 -  History, physical, social or lab findings suggestive of any medical or psychological
 condition that would, in the opinion of the PI, make the candidate ineligible for the
 study.