Frontal Brain Mitochondrial Activity as a Transdiagnostic Biomarker of Psychopathology and Impaired Cognition: A Proof-of-Concept Study Using Functional Near-Infrared Spectroscopy

Mitochondrial dysregulation has been demonstrated to be implicated in a variety of psychiatric and neurocognitive disorders, including depression and dementia. However, brain mitochondrial activity in vivo and its relationship to psychopathology and cognitive impairment have rarely been investigated so far. Here, we aimed to assess brain mitochondrial activity and indices of mitochondrial-vascular coupling as biomarkers of psychopathology and impaired cognition in a transdiagnostic human sample in vivo using optical functional neuroimaging with broadband near-infrared spectroscopy. In 65 adults with (n= 29) and without (n = 36) an acute psychiatric disorder, during resting state and cognitive tasks (assessing attention, processing speed, verbal fluency), we recorded left prefrontal cortex mitochondrial activity (measured as change in the oxidation state of cytochrome c oxidase) and vascular activity (measured via change in the oxy- and deoxyhemoglobin difference score). We derived three indices of mitochondrial-vascular coupling: concurrent mitochondrial-vascular activity, mitochondrial-vascular mismatch, and correlation. During the cognitive tasks, a reduced intraindividual mitochondrial-vascular correlation was related to impaired cognition. At rest, higher mitochondrial activity was associated with impaired cognition and higher emotional dysfunction. In addition, higher vascular activity at rest was linked to impaired cognition, higher externalizing symptoms and the acute psychiatric disorder group. The results of this proof-of-concept study provide initial evidence for a dysregulated cellular energy production in adults with impaired cognition and higher emotional dysfunction. Further large-scale studies should replicate these findings and clarify whether mitochondrial biomarkers can advance preventive, predictive, and precision medicine.