Effect of Metabolic State on Anxiety in Human Subjects

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.