Molecular and Neuroimaging Correlates of Bipolar Disorder: Linking Inflammation, Mitochondria, and Brain Circuitry

Bipolar affective disorder (BD) is a severe mental illness characterized by recurrent episodes of mania, hypomania, and depression, accompanied by progressive neurobiological changes that go beyond the classical concepts of neurotransmitter dysregulation. Increasing evidence points to the key role of the interaction between inflammatory processes, mitochondrial dysfunction, and disturbances within neural networks in the pathogenesis, course, and treatment response of BD. Neuroinflammatory processes, including elevated levels of pro-inflammatory cytokines, chemokines, and microglial activation, are consistently reported in patients with BD and linked to cognitive impairment, accelerated neuroprogression, and treatment resistance. At the same time, mitochondrial abnormalities-such as impaired oxidative phosphorylation, excessive production of reactive oxygen species, and disturbances in calcium homeostasis-contribute to oxidative stress, synaptic dysfunction, and increased neuronal vulnerability, forming the biological substrate of mood instability. Findings from neuroimaging studies provide consistent evidence of structural and functional alterations within the cortico-limbic networks regulating emotions, including the prefrontal cortex, anterior cingulate cortex, amygdala, and hippocampus. Importantly, a growing number of studies demonstrate correlations between neuroimaging changes and inflammatory and metabolic biomarkers, making it possible to link molecular pathology with dysfunctions at the level of neural networks. The use of multimodal methods-encompassing structural and functional magnetic resonance imaging, spectroscopy, and molecular analyses-allows for a more precise explanation of these complex interactions and the identification of biomarkers of clinical states, progression, and treatment response. This review synthesizes current knowledge on the molecular and neuroimaging correlates of BD, emphasizing the interdependence of inflammatory processes, mitochondrial function, and neural networks. The integration of molecular biomarkers with imaging-based phenotyping opens new perspectives for precision medicine in BD.