Broadband Near-Infrared Spectroscopy in Vivo Study of Brain Mitochondrial Oxidative Metabolism and Hemodynamics in Bipolar Disorder

Mitochondrial oxidative dysfunction is increasingly implicated in the neuropathophysiology of bipolar disorder (BD), yet in vivo brain assessments of cerebral oxidative metabolism and its relationship with oxygenation have been limited. Here, brain broadband near-infrared spectroscopy (bNIRS) non-invasively measured oxidation of the key enzyme of the mitochondrial electron transport chain, mitochondrial complex IV cytochrome-c-oxidase (oxCCO), alongside oxyhemoglobin (HBO) and deoxyhemoglobin (HBR) measures, in vivo in adults with BD and healthy comparison (HC) during visual stimulation. The relationship between oxCCO and the hemodynamic measures was assessed. During visual stimulation, participants with BD showed significantly higher elevations in oxCCO and significantly lower relative power (concurrence between oxCCO and oxygen use) compared to HC participants, a pattern also observed in euthymic BD participants, suggesting a trait difference in BD. The BD participants also had significantly higher levels of peripheral blood lactate, even when oxCCO levels were high, unlike the association observed for HC participants, which would be expected if oxidative phosphorylation was providing energy to meet neural demands. Together, these findings suggest that to meet neural energy demands, mitochondria in BD exhibit oxygen consumption that is not efficiently coupled to ATP production, and instead shift toward an energetically inefficient process, aerobic glycolysis. By enabling the simultaneous assessment of mitochondrial metabolism and hemodynamics, bNIRS provided a new, scalable, non-invasive tool to uncover mechanisms of neuroenergetic dysfunction in BD. This approach may facilitate the identification of novel mechanistic targets and advance biomarker development for more personalized interventions in mood disorders and potentially other neuropsychiatric disorders.