The Brain on Whole Body Hyperthermia: A Neuroimaging Study

The Investigators have observed in an open trial that a single session of whole body
hyperthermia (WBH) induced rapid antidepressant effects that persisted for at least a week
in patients with major depression (MDD) severe enough to warrant inpatient hospitalization.
In addition to reducing depression, the single session of WBH induced a prolonged reduction
in mean core body temperature, consistent with basic science data from our group suggesting
that hyperthermia activates a skin-to-brain pathway that targets specific serotonergic
nuclei in the raphe. In animal models, these nuclei have been shown to be important for mood
and body temperature regultion. Consistent with this known anatomy in our preliminary study
in depressed patients, reductions in core body temperature were highly correlated with
reductions in depressive symptoms over the same time period (one week post WBH). Moreover,
patients with higher mean core body temperature prior to treatment had enhanced
antidepressant effects. Because increased body temperature is an outcome of poor functioning
in the skin-to-brain pathway activated by WBH our data suggest that WBH may actually
sensitize this pathway in ways that promote changes in brain functioning known to promote
emotional well-being. The results of our first open trial have encouraged us to conduct a
larger, more rigorous placebo-controlled, double blind study of WBH for MDD, which is
currently underway at the University of Arizona Medical School. In addition to assessing
effects on depressive symptoms in comparison to a sham condition, this study examines the
effect of WBH on body temperature, autonomic nervous system function, thermoregulatory
cooling, immune, neuroendocrine and monoamine functioning and real-world daily social
behavior.

Missing from our assessments in this ongoing double-blind study is any measure of the impact
of WBH on brain function. The current proposal addresses ths gap in our investigative
portfolio by proposing to conduct a second, randomized trial of active vs. sham WBH that
will examine the impact of WBH on measures of brain function known from prior studies to be
important for both depression and its treatment. These measures will include functional
magnetic resonance imaging (fMRI) analyses of resting state brain connectivity as well as
assessments of concordance between subgenual anterior cingulate cortex and autonomic nervous
system function assessed by electrocardiogram (EKG). Prior to these fMRI assessments a
structural MRI will be obtained.

The investigators propose to conduct this fMRI/EKGtudy in 30 students (15 males/15 females)
recruited from the PSYC150A1 Mass survey, which allows University of Arizona students an
opportunity to serve as research subjects for course credit. These potential participants
will be between the ages of 18 and 30 and will have self-reported depressive symptomatology
of at least moderate severity, as reflected in a Beck Depression Inventory (BDI) II score ≥
14. Participants will be medically healthy with no history of bipolar I disorder,
schizophrenia or active substance dependence. Participants will complete questionnaires one
week prior to, the day of, and one week following a single administration of either WBH or
sham WBH (delivered with a 1-to-1 ratio). On the morning prior receiving WBH or sham WBH and
again 24 hours later all subjects will undergo fMRI/EKG assessment. This design will allow
us to evaluate the acute brain effects of WBH and to evaluate the relationship between these
changes and both acute and short term (i.e. one week post treatment) improvements in mood.

Inclusion Criteria:

- Male or female aged 18-30.

- Able to understand the nature of the study and able to provide written informed
consent prior to conduct of any study procedures.

- Fluent English Speakers (for fMRI purposes)

- Right-handed (for fMRI purposes)

- For women of child-bearing potential (i.e., one who is biologically capable of
becoming pregnant), must be willing to use a medically acceptable form of birth
control or practice abstinence for the duration of her participation in the trial.

- Beck Depression Inventory-II Score of ≥14 (Moderate depression)

- Normal or corrected to normal vision and normal hearing (for fMRI purposes)

Exclusion Criteria:

- Any of the following diagnoses, as identified by the intake evaluation conducted or
study assessments:

- A diagnosis claustrophobia severe enough that it would impair ability to be in the
Heckel HT3000 hyperthermia device and/or the fMRI machine.

- A current (or within 12 months prior to the Screening visit) diagnosis of Anorexia
Nervosa or Bulimia Nervosa

- A current (within 1 month prior to screening visit) diagnosis of substance dependence

- Lifetime history of schizophrenia or bipolar I disorder

- Use of psychotropic medications within 2 weeks of screening (8 weeks for fluoxetine)
except for use of benzodiazepine or non-benzodiazepine sleeping agents

- Subject has a medical condition or disorder that:

- Is unstable and clinically significant, or:

- Could interfere with the accurate assessment of safety or efficacy of treatment,
including:

- individuals who are using prescription drugs that may impair thermoregulatory
cooling, including diuretics, barbiturates, and beta-blockers, or antihistamines,

- individuals with cardiovascular conditions or problems (uncontrolled hypertension,
congestive heart failure, or documented evidence of coronary artery disease)

- individuals with chronic conditions/diseases associated with a reduced ability
initiate thermoregulatory cooling, including Parkinson's, multiple sclerosis, central
nervous system tumors, and diabetes with neuropathy,

- hemophiliacs/individuals prone to bleeding,

- individuals with a fever the day of study intervention,

- individuals with hypersensitivity to heat,

- individuals with recent acute joint injury,

- individuals with enclosed infections, be they dental, in joints, or in any other
tissues,

- individuals with silicone or saline implants as these can overheat and lead to
burning

- Clinically significant, in the investigator's opinion, abnormal findings on screening
laboratory tests or physical exam as presented to the research team.

- Need for any non-protocol psychotropic medication once enrolled, with the exception
of benzodiazepine or non-benzodiazepine hypnotics used at a stable dosage.

- Women who are pregnant (HCG pregnancy test at screening, or lactating, or who plan to
become pregnant during the study.

- Current participation in any clinical trial that might impact results of this one,
which includes participation in another clinical trial for depression, as well as
drug trials with agents that might affect mood or regulation of body temperature.

- Reasonable likelihood for non-compliance with the protocol for any other reason, in
the opinion of the Investigator, prohibits enrollment of subject into the study.

- Obesity and overall size of subject. It will be up to the PI's discretion will
consider BMI, waist circumference, and body fat composition when determining
eligibility and safety of the individual.

- History of peripheral circulatory disease, for example peripheral vascular disease,
deep vein thrombosis (DVT), or lymphedema.

- History of a cerebral vascular accident

- History of stroke, epilepsy or cerebral aneurisms

- Cancer in the last five years.

- Diabetes mellitus types I or II

- Any clinically significant autoimmune disease (compensated hypothyroidism allowed)

- Any prior history of neurological disorder, traumatic brain injury associated with an
alteration of consciousness, serious medical illness that could result in cognitive
impairments, and drug or alcohol dependence.

- Any potential risks for MRI, including metal fragments, implants, pins or plates,
pacemakers, or metal dental work.