Cognitive, Emotional, and Neural Responses to Acute Inflammation

The inflammatory response of the immune system is responsive to stress and it impacts brain
function. Animal studies have shown that inflammation appears to alter threat- and
reward-related brain activity. Accumulating evidence points to inflammatory proteins,
specifically cytokines, as key players in this relationship. Although cytokines are typically
too large to pass through the blood brain barrier (BBB), they can influence brain function
and structure by transmitting signals from peripheral systems to the brain.

The administration of endotoxin within the polysaccharide form of Salmonella typhi
vaccination provides an ideal model for studying the causal effects of short-term
inflammation on thinking patterns (i.e., cognition) and emotions in the brain. Endotoxin is a
component of the cell walls of Gram-negative bacteria, which promotes the production of
pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha
(TNF-α) via toll-like receptor-4 (TLR-4) activation and nuclear factor- κB (NF-κB) signaling.

To examine the effects of acute inflammation on brain functioning, 24 healthy participants
will be recruited. The investigators will will randomize participants to placebo or
inflammatory challenge using polysaccharide typhoid vaccine (i.e., endotoxin) and will use
validated behavioral tasks and questionnaires to assess threat and reward sensitivity. They
will assess chronic resting levels of inflammation as well as the inflammatory response to
Salmonella typhi vaccination.

Inclusion Criteria:

- Healthy individuals (free of chronic illness or lifetime history of psychiatric
disorder)

- Non-smokers

Exclusion Criteria:

- Lifetime history of an psychiatric disorder with psychotic features, bipolar disorder,
obsessive-compulsive disorder, alcohol or substance dependence, or a history of
alcohol or substance abuse within the past 2 years.

- Currently exposed to recurrent trauma or have been exposed to a traumatic event within
the past 3 months, or has current diagnosis of PTSD.

- Diagnosis of sleep apnea, neurological disorder, systemic illness affective central
nervous system function, and/or anemia.

- Any suicidal or homicidal ideation within the past year.

- Subjects currently receiving selective serotonin reuptake inhibitors (SSRIs),
benzodiazepine receptor agonists, anticonvulsants, atypical antipsychotic medication,
any antidepressant medication including trazodone, or any psychotropic medication.

- Termination of SSRIs, benzodiazepine or benzodiazepine receptor agonists,
anticonvulsants, atypical antipsychotic medication, any antidepressant medication
including trazodone in the last month, or plans to start these medications during the
course of the study.

- Contraindications to fMRI, including severe claustrophobia and presence of
ferromagnetic objects in the body that would interfere with magnetic resonance
examination and/or cause a safety risk (e.g., pace makers, implanted stimulators,
pumps, extensive dental work, upper body tattoos).

- Contraindications to typhoid vaccine, which include acute febrile illness within the
past two weeks, disorders characterized by a deficiency to ability to mount a humoral
or cell-mediated immune response, use of anti-malarial medications in the past six
months, antibiotics in past three months, a history of hypersensitivity to typhoid
vaccine or any other vaccine, pervious immunization with whole-cell typhoid or live,
oral typhoid vaccines, vaccination with the polysaccharide version of the typhoid
vaccine within the past 3 years.

- Conditions or use of substances that may be associated with inflammation, including
drugs that affect the immune system.

- Any chronic medical illness.

- Having a body mass index (BMI) over 30.

- Individuals who work the night shift