Mitochondria Make You Think: An [18F]BCPP-EF Positron Emission Tomography Study of Mitochondrial Complex I Levels and Brain Activation during Task Switching (Whitehurst, Chika Onwordi, 2025)

Shatalina E; Whitehurst T; Chika Onwordi E; Whittington A; Mansur A; Arumuham A; Reis Marques T; Gunn RN; Natesan S; Nour MM; Rabiner EA; Wall MB; Howes OD; 

Biological psychiatry. Cognitive neuroscience and neuroimaging [Biol Psychiatry Cogn Neurosci Neuroimaging] 2025 Feb 24. Date of Electronic Publication: 2025 Feb 24.

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Background: Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level-dependent (BOLD) response and impairments in cognition. This study aims to investigate the relationship between mitochondrial complex I levels, cognitive function, and associated neural activity during task switching in healthy humans.

Methods: Cognitively healthy adults (n=23) underwent [18F]BCPP-EF PET scans and functional magnetic resonance imaging (fMRI) while performing a task-switching exercise. Task performance metrics included switch cost and switching accuracy. Data were analysed using linear mixed-effects models and partial least squares regression (PLS-R).

Results: We found significant positive associations between [18F]BCPP-EF VT and the task-switching fMRI response (β=3.351, SE=1.01, z=3.249, p=0.001). Positive Pearson's correlations between [18F]BCPP-EF VT and the fMRI response were observed in the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). [18F]BCPP-EF VT across task-relevant regions was associated with task switching accuracy (PLS-R, R2=0.48, RMSE=0.154, p=0.011) and with switch cost (PLS-R, R2=0.38, RMSE=0.07, p=0.048).
Conclusions: Higher mitochondrial complex I levels may underlie an individual's ability to exhibit a stronger BOLD response during task switching and are associated with better task-switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction that should be tested in future studies.