Broadband Near Infrared Spectroscopy to Elucidate the Role of Cortical Brain Cytochrome C Oxidase Activity in the Pathophysiology of Bipolar Disorder

About This Grant

SUMMARY Bipolar disorder (BD) is a major public health problem, as it causes significant disability and suicide risk. There is a great clinical need to improve the treatment for the depressed phase of BD. The pathophysiology of BD is largely unknown, and understanding its pathophysiology could help to advance treatment. Previous neuroimaging and post mortem brain studies have provided indirect evidence that mitochondrial pathology may be occurring as part of BD’s pathophysiology. Recent animal model studies indicate that mitochondrial pathology can induce behavioral symptoms of BD. This study will use broadband Near Infrared Spectroscopy (bNIRS), a novel optical neuroimaging research tool, to directly measure cytochrome c oxidase (oxCOX) signal as an index of mitochondrial activity in the brain. Our preliminary data with the technique suggests that participants with BD may have lower oxCOX signal than healthy volunteers (HV’s), and that oxCOX signal had an inverse association with depression severity. Previous studies of BD have indicated differences in blood indices of mitochondrial pathology, including lower Mitochondrial Health Index (MHI). MHI is a composite measure of both mitochondrial enzymatic activities and mitochondrial DNA copy number within peripheral blood monocyte cells, and it was developed by a co-investigator on the project, Martin Picard. This project will test whether MHI is associated with brain oxCOX signal to assess whether a brain mitochondrial pathology may be caused by or part of a broader systemic mitochondrial abnormality. Other aspects of BD’s pathophysiology, including levels of life stress and past course of mood episodes may be related to mitochondrial pathology based on previous data, and will be measured here. bNIRS is low cost and non-invasive, and it does not require specialized facilities or operational training. It therefore has broad potential for clinical research and treatment use. A tool to track the clinical course of BD would allow for clinical decisions to be based on an objective measure, improving cost and delivery of care. This study aims to advance the bNIRS technique towards this purpose. 30 participants with BD in a major depressive episode and 20 HVs will be recruited. Participants will receive bNIRS using hypocapnia and hypercapnia challenges, the Bipolar Depression Rating Scale (BDRS), the STRAIN, venipuncture and a thorough clinical history. BD participants will then receive a structured clinical treatment with a medication that is FDA approved for depression in BD. bNIRS, MHI and BDRS will be repeated at weeks 3 and 6 of treatment. Aim 1 will be to determine whether brain mitochondrial function in the prefrontal cortex, measured by bNIRS, is lower in BD than HVs. Aim 2 will be to assess whether bNIRS can be used to track mood symptoms during an acute treatment course of depression in BD, and whether it is associated with depression severity. Aim 3 will be to determine if the MHI is associated with brain oxCOX signal in BD. The Exploratory Aim will assess whether bNIRS oxCOX activity is associated with either measures of life stressors on STRAIN, or duration and severity of past mood episodes.