The Brain on Whole Body Hyperthermia: A Neuroimaging Study
Condition: Major Depression
MeSH terms: Hyperthermia; Fever
Study type: Interventional

Summary: 
      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 have been shown in animals to be
      important for mood and body temperature regulation. 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 suggests 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. 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.
    

Detailed description: 
      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.
    

Intervention name(s): High intensity whole-body infrared heating; Low intensity whole-body infrared heating; Functional Magnetic Resonance Imaging (fMRI) and electrocardiogram (EKG); Questionnaires
Intervention type(s): Device; Device; Device; Other
Intervention description(s): The Whole Body Hyperthermia system uses water-filtered infrared-A (wIRA) heat radiation. The rise in the body's core temperature is correspondingly rapid and well-tolerated. There are two phases of the thermal challenge, 1) Irradiation phase during which the patient lies recumbent with his/her head positioned outside the tent. The wIRA irradiators are arranged above the exposed upper part of the body; and 2) Heat retention phase during which the patient lies in the chamber with the walls of the tent positioned to retain heat. Core body temperatures will be raised to those comparable to a mild fever 37.8-38.5°C.; Attenuated heating using only heating coils at the bottom of the Heckel device. This results in only a minor increase in skin temperature and no increase in core body temperature. The participant will still feel heat and will see similar lighting and hear similar sounds as those occurring during actual WBH, and will be in the chamber for the same period of time.; A standard magnetic resonance imaging (fMRI) machine will be used to take images of the brain. An standard EKG (compatible with the fMRI machine) will be used to take measurements of cardiac vagal control.; Weekly questionnaires to assess changes in depression, mood, perceptions of self and quality of life will be administered.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Whole Body Hyperthermia; Functional Magnetic Resonance Imaging; EEG