Brain Bioenergetic Response to Hypoxic Stress in Bipolar Disorder

Principal Investigator: Perry Renshaw
Keywords: Bipolar Disorder , Veterans , Hypoxia , Altitude Department: Adult Psychiatry
IRB Number: 00100784 Co Investigator: Younghoon Sung
Specialty: Psychiatry
Sub Specialties: Mood Disorders
Recruitment Status: Not yet recruiting

Contact Information

Colin Riley

Brief Summary

Embedded in the Rocky Mountain (VISN 19) Mental Illness Research, Education and Clinical Center (MIRECC) and its mission is to reduce suicidal behavior in Veterans, this proposal is a competative renewal of I01-CX000812, “Brain Chemistry and Altitude in Bipolar Disorder.” Having studied Veterans with bipolar disorder (BD) who are ‘chronically’ adapted to living at moderate altitude (Salt Lake City, UT; 4,700 ft) vs. Sea Level (Boston, MA; 44 ft), we now seek to build upon and extend our results, by investigating a phenomenon that more closely resembles the moment-to-moment cerebral bioenergetic demands of daily life: the brain’s capacity to adapt, when ‘acutely’ exposed to oxidative stress during a single brain scan session, in BD vs. Healthy Controls (HC).

Improved understanding of the effects of oxidative stress in BD may provide critical insights, as evidence is accumulating that implicates it in BD pathophysiology. Likewise elucidating the mechanisms, and interactions between brain bioenergetics, acute hypoxic stress and altitude could be applicable to a variety of brain diseases of concern to the Veterans Health Administration (VHA). For example, mitochondrial dysfunction is linked to Parkinson, Alzheimer and Huntington disease, and Amyotrophic Lateral Sclerosis. Mitochondrial homeostasis is also disrupted in Traumatic Brain Injury (TBI), and contributes to the cognitive degeneration seen in obesity and diabetes mellitus. Given mitochondrial dysfunction in BD, and its status as a treatment target, our goal is to identify specific bioenergetic targets to assist the development of novel BD interventions. Hypobaric hypoxia is the term used to describe the fact that as altitude increases, the atmospheric pressure falls, and with it the partial pressure of inspired oxygen (PiO2), which places oxidative stress on the brain. It is a fact that HC in Salt Lake City have a significantly lower mean partial pressure of oxygen (PaO2) in arterial blood (79.2 mm Hg), as compared to HC who reside near Sea Level (99.8 mm Hg). This stems from the fact that at the altitude of Salt Lake City, PiO2 and therefore the availability of oxygen, is ~85% of the PiO2 at Sea Level. When the oxidative stress intrinsic to BD is combined with altitude, the results may be additive. This view is supported by our finding that suicide in BD occurs at a higher mean altitude than other major mental disorders, suggesting hypobaric hypoxia renders BD more severe, or its treatment less effective -- or both. 

To support neuronal activity, the creatine kinase (CK) reaction rapidly converts phosphocreatine (PCr) to adenosine triphosphate (ATP). CK is coupled to, and serves as the temporal and spatial buffer of oxidative phosphorylation, the chief source of ATP in the brain that consumes 80-90% of cellular oxygen. This reliance means ATP levels are sustained for only ~1 minute without oxygen, unless stabilized by CK. We chose phosphorus-31 magnetic spectroscopy (31P-MRS) for this proposal, because 31P-MRS is the only method capable of detecting changes to ATP and PCr in vivo, occurring in response altered experimental conditions.

Our current study sought to determine the effect on brain bioenergetics in BD and HC, of chronic exposure to hypobaric hypoxia at moderate altitude (4,700 ft). Our results, detailed below in the Progress Report, indicate the majority of significant differences in 31P-MRS metabolites are based on altitude, i.e. between-site differences, rather than between-group diagnostic differences in BD vs. HC. These results are intriguing, and converge with data showing that cells from BD patients exhibit an aberrant response to glucose deprivation: BD patient cells down-regulate transcripts for mitochondrial respiration proteins, whereas HC cells up-regulate them. For this competitive renewal, in parallel with ‘glucose deprivation’ as a test of respiratory chain function, we propose to test the CK system. Yuksel et al. found this system fails to replenish ATP from PCr, in BD patients receiving photic stimulation to place an acute energetic stress on visual cortex. Inspired by that work and as described in Preliminary Studies, we designed a method that enables us to place acute hypoxic stress on the brain, and measure changes in ATP and PCr in response, all during a single 31P-MRS scan session. 

We plan to pair our acute hypoxic stress paradigm, with a peripheral measure of adaptation to altitude. At a cellular level, hypoxia-inducible factor (HIF-1) is upregulated to control transcription of genes that participate in the adaptation to hypoxia. Interestingly, HIF-1 mRNA levels in blood are increased in BD, and then decrease with successful treatment. We propose to examine the response to acute hypoxia, by comparing the 31P-MRS metabolites PCr and ATP at simulated Sea Level conditions vs. 10,000 ft altitude, and exploring their association with serum HIF-1 levels in Veterans with BD and HC. The goal is to delineate specific bioenergetic treatment targets for BD in the brain, through pursuit of the following Specific Aims:

Aim 1: To measure changes in PCr and ATP, that occur in response to acute hypoxic stress in BD and HC;

Aim 2: To quantity peripheral HIF-1 levels in BD and HC Veterans residing at moderate altitude;

Aim 3: To explore the association between the and peripheral HIF-1 levels in BD and HC Veterans.

Using 31P-MRS and PiO2 of 24 (or higher)% and 16(+2)% to simulate Sea Level and 10,000 feet, respectively, combined with analysis of peripheral HIF-1 levels in BD and HC, will enable us to investigate the following Hypotheses:

1) Veterans with BD will fail to replenish ATP levels from PCr, following exposure to acute hypoxic stress;

2) Peripheral HIF-1 levels will be significantly elevated in BD Veterans, compared with HC; and

3) Hypoxic stress-induced alterations in ATP and PCr will correlate with peripheral HIF-1 levels.

Inclusion Criteria

General Inclusion Criteria for All Study Subjects:

1) Age 18 to 65 years;

2) Absence of unstable medical or neurological conditions as determined by medical history, physical examination, and laboratory tests including complete blood count, blood chemistry, and urinalysis;

3) Capable of providing valid informed consent, which includes compliance with the study requirements listed in the consent form.

General Inclusion Criteria for Bipolar Disorder Subjects:

1) Diagnosis of bipolar I disorder, confirmed by clinical interview and structured clinical interview;

2) A euthymic or depressive mood state at time of screening, based on the judgment of the study physician, and a Young Mania Rating Scale (YMRS) score < 7.

Specific Altitude-Related Inclusion Criteria for All Study Subjects:

1) Resident of the Inter-Mountain West for a minimum of 2 months; 2) No out-of-region travel for 2 months prior to study entry;

3) No air travel within 2 months of study enrollment, or during study participation.

Exclusion Criteria

General Exclusion Criteria for All Study Subjects:

1) Alcohol or substance use disorder within 3 months of enrollment in the study as identified by SCID 5 diagnostic assessment at screening visit (based on DSM-5 criteria), or a positive screen for drugs of abuse at the screening visit;

2) Body mass index (BMI) of 300 pounds or greater;

3) History of known or suspected mental retardation;

4) Contraindication to MRI scanning, e.g. ferrometallic implant;

5) History of clinically significant claustrophobia;

6) History of pulmonary disease such as chronic obstructive pulmonary disease;

7) Concurrent participation in another clinical study in which the subject is, will be, or has been exposed to an investigational or a non-investigational drug or device within 4 weeks prior to brain scanning;

8) Pregnant women and breastfeeding mothers will be excluded.

Exclusion Criteria for All Bipolar Disorder Subjects:

1) Substance use disorder within the previous 3 months;

2) Any of the following BD specifiers at the time of screening: a manic episode, rapid cycling, seasonal pattern, or without inter-episode recovery.

Exclusion Criteria for Healthy Comparison Subjects:

1) Current or past psychiatric or substance use disorder;

2) First-degree relative with a known or suspected psychiatric or substance use disorder;

3) History of treatment with psychotropic medication.