The Role of Environmental Temperatures in Respiratory Control

Optimizing Mind-Body Interactions in Respiratory Control During Operationally Relevant Environmental Stressors

Warfighters are frequently exposed to environments and life-support systems that increase breathing resistance and the work of breathing (WOB), such as aircraft on-board oxygen generation systems and underwater breathing apparatuses. Elevated WOB increases the perception of breathing difficulty (dyspnea) and has been associated with impaired cognitive performance, including slower reaction time and reduced accuracy during attention-demanding tasks. These effects are particularly concerning in operational settings that require rapid decision-making and precise motor responses.

Despite growing recognition of this issue, critical gaps remain regarding strategies to mitigate the perceptual and cognitive consequences of elevated inspiratory resistance, especially under realistic operational stressors. The objective of this study is to determine whether exposing individuals to thermal stress alters breathing perception and cognitive performance during inspiratory resistance. Participants will perform inspiratory resistance breathing under thermoneutral, heat, and cold conditions to determine whether thermal stress amplifies WOB, breathing perception, and cognitive impairment.

Study Overview

• Status: Not yet recruiting
• Conditions: Work of Breathing
• Intervention / Treatment: Other: Thermoneutral temperature environment; Other: Cold temperature environment; Other: Hot temperature environment

Detailed Description

Warfighters often face thermal stressors that increase the WOB, even with life-support systems in place. Both cold and heat stress elevate the WOB independently, without requiring increased inspiratory resistance. Cold stress stimulates ventilation and causes a biphasic bronchiolar response: inhaling cold air during hyperventilation leads to initial bronchodilation followed by bronchoconstriction, tightening the bronchioles and increasing airflow resistance, and thus the WOB. Warfighters are also exposed to extreme heat and hyperthermia-induced hyperventilation occurs when core body temperature reaches around 38.0°C, significantly correlating with increased WOB during heat stress. Warfighters frequently experience these environmental stressors alongside elevated breathing resistance, especially during underwater diving missions in varying temperatures or in high-performance aircraft with OBOGs exposed to extreme heat.

A critical gap in knowledge exists regarding whether high inspiratory resistance combined with thermal stress amplifies the WOB, altering the perception of breathing and cognitive and physiological responses. The study will investigate the WOB, breathing perception, cognitive function, and physiological responses under combined inspiratory resistance and thermal stress (thermoneutral, heat, and cold). It's hypothesized that WOB will increase during heat and cold stress, resulting in greater perceptions of breathing difficulty and decreased cognitive performance compared to thermoneutral conditions.

Participants will complete 4 study visits: a screening/familiarization visit (Study Day 0) followed by three experimental visits (Study Day 1, Day 2, and Day 3). Participants will be instructed to avoid caffeine, alcohol, stimulant medication, pain/anti-inflammatory medication, cannabis and cannabis related products, and vigorous exercise for at least 24 hours prior to experimental visits. On Study Day 0, participants will complete a short familiarization breathing task in which they will breathe for 10 minutes through an 8-10mm hole at the end of a customized device, generating a pre-determined inspiratory resistance of 6-9.5 centimeters of water per liter per second (cmH2O/L/s). During the breathing task, cerebral vascular, cardiovascular and autonomic activity responses will be measured. Every 5 minutes during the breathing test, participants will be asked to rate breathing intensity and unpleasantness, and perform an inspiratory capacity maneuver. Cognitive assessments will be administered every10 minutes. After the breathing task, participants will complete lung and respiratory muscle function tests.

Prior to the experimental visits, participants will be randomized to the order in which they are exposed to the interventional conditions (hot, cold, or thermoneutral). Upon arrival, an esophageal balloon will be placed to measure the pressure around the heart and lungs. Participants will then be placed into an environmental chamber (to control humidity) while wearing a special suit which allows different temperatures of water to be circulated through tubes which will expose them to the temperature conditions for roughly 30 minutes before starting the full-length breathing tasks. During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity. During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity. The breathing task will commence when esophageal temperature reaches -1°C and -2°C relative to baseline esophageal temperature. During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity. The breathing task will commence when esophageal temperature reaches +1°C and +2°C relative to baseline esophageal temperature. At each experimental visit, participants will complete a full-length breathing task, in which they inspire against a predetermined resistive load for 60 minutes. Biometric monitoring will be continuously performed, and cognitive assessments and participant ratings during the breathing tasks will be performed at 45- and 90-minutes of the condition exposure. A 7 day washout period will be observed between the experimental visits.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Timothy D Mickleborough, PhD; Phone Number: 812-855-0753; Email: tmickleb@iu.edu

Study Locations

• United States
  • Indiana
    • Bloomington, Indiana, United States, 47405
      • Multidisciplinary Engineering and Sciences Hall (MESH)
      • Contact: Scott M Clarke; Phone Number: 812-856-3244; Email: scotclar@iu.edu
      • Contact: Zachary J Schalder, PhD; Phone Number: 812-855-6953; Email: zschlade@iu.edu
      • Principal Investigator: Timothy D Mickleborough, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Between the ages of 18-40 years old.
• English speaking and reading.
• Self-reported weekly activity of at least 120 minutes/week of high intensity exercise for the previous 2 years.
• Normal pulmonary function assessed by a resting forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) > 75% of predicted.
• Normal cognitive function assessed using the Montreal cognitive function test [18].
• Body mass index (BMI) ≤ 35 kg/m2.
• Females with a regular menstrual cycle that ranges from 21-35 days (eumenorrhea)

Exclusion Criteria:

• History of smoking or recreational smoking, cardiovascular disease, renal disease, pulmonary disease (including asthma or exercise-induced asthma), neurological disease, and metabolic disease.
• Are pregnant or could possibly be pregnant by self-report.
• Are color blind.
• Known allergy or hypersensitivity latex.
• Take selective serotonin reuptake inhibitors, stimulant medication, antibiotics, and chronically consume pain medication (Aleve, Tylenol, etc.).
• Resting blood pressure of > 130mmHg systolic or 90 mmHg diastolic and/or resting pulse rate of > 100 bpm.
• Females with irregular menstrual cycles (oligomenorrhea) that ranges from 36-90 days, and females with the absence of a menstrual cycle (amenorrhea).
• Taking birth control for the sole purpose of period cessation (eg., Mirena IUD)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Thermoneutral temperature, then Cold temperature, then Hot temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.
Active Comparator: Thermoneutral temperature, then Hold temperature, then Cot temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.
Active Comparator: Cold temperature, then Thermoneutral temperature, then Hot temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.
Active Comparator: Cold temperature, then Hot temperature, then Thermoneutral temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.
Active Comparator: Hot temperature, then Thermoneutral temperature, then Cold temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.
Active Comparator: Hot temperature, then Cold temperature, then Thermoneutral temperature; Participants will complete 3 experimental visits at which they will complete a breathing task under an assigned temperature condition. The order of condition exposure will be assigned via randomization.	Other: Thermoneutral temperature environment; During thermoneutral conditions 34°C water will be perfused through special suit while participants resting the chamber set to 24°C and 40% room humidity.; Other: Cold temperature environment; During the cold condition, 4°C water will be perfused through the special suit while participants rest in the chamber set to 4°C and 10% room humidity.; Other: Hot temperature environment; During the hot condition, 50°C water will be perfused through the special suit while participants rest in the chamber set to 40°C and 40% room humidity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Stroop Color-Word Test Time Performance	Time performance on the Stroop Color-Word Test (min:sec) will be measured every 45 minutes during each experimental breathing task.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Stroop Color-Word Test Error Performance	The number of errors on the Stroop Color-Word Test will be measured every 45 minutes each experimental breathing task.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Perception of Dyspnea Intensity	Participants will rate perception of dyspnea (breathing) intensity on a visual analog scale (VAS) every 45 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line (100mm), indicating their breathing perception from "not noticeable" (0mm) to "maximal imaginable intensity" (100mm).	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Perception of Dyspnea Unpleasantness	Participants will rate perception of dyspnea (breathing) unpleasantness on a visual analog scale (VAS) every 45 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line(100mm), indicating their breathing perception from "not unpleasant"(0mm) to "maximal imaginable unpleasantness" (100mm).	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Diaphragm Thickness	Diaphragm thickness will be measured via Doppler ultrasound of the10th/11th rib space during functional residual capacity (FRC; rest) and end-inspiration, as well as during the maximal inspiratory pressure (MIP)test from FRC before and after each condition.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Heart Rate Variability	Heart rate variability (beats per minute) will be measured continuously during each breathing task via 3-lead electrocardiograph (ECG).	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Peripheral Oxygen Saturation	Peripheral oxygen saturation will be measured continuously during each breathing task via pulse oximetry.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Blood Pressure - Brachial Artery	Blood pressure will be measured every 10 minutes during each breathing task via a standard blood pressure cuff and auscultation of the brachial artery.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Blood Pressure - Finger Photoplethysmography	Blood pressure will be measured continuously during each breathing task via finger photoplethysmography.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Heart Rate	Heart Rate will be measured continuously during each breathing task by 3-lead electrocardiograph (ECG).	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Cerebral Blood Oxygen Kinetics	Oxyhemoglobin and deoxyhemoglobin (uptake/extraction, uM) will be measured continuously via near-infrared spectroscopy (NIRS) of the pre-frontal cortex during each breathing task.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)
Change in Cerebral Blood Velocity	Bilateral transcranial Doppler Ultrasound will be used to continuously measure middle and posterior cerebral artery blood velocity during each breathing task. The ultrasound transducers will be placed on both sides of the head at the temporal windows and the positions will be fixed using a transducer holder.	Before and after each breathing task on Days 1, 2, 3 (each approximately 90 minutes in duration)

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: United States Department of Defense

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2028
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: March 10, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive Performance; Inspiratory Resistance; Dyspnea Perception; Thermal Stress
• Other Study ID Numbers: 28381 - Aim 3; FOAAFRLAFOSR20240007 (Other Grant/Funding Number: Air Force Office of Scientific Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The plan to share individual participant data (IPD) is still unknown. However, if other researchers request IPD, we will evaluate that request and determine to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes