Functional Magnetic Resonance Imaging Signal Typically Viewed as "Noise" Has Clinical Relevance in Psychiatry

Functional magnetic resonance imaging (fMRI) aims to identify biomarkers of neuropsychiatric illnesses, including substance use disorders; however, fMRI's clinical utility remains limited. One underexplored aspect of the fMRI signal is the systemic low-frequency oscillation (sLFO), a global physiological signal historically treated as noise but linked to vascular and autonomic function.

Across 4 independent datasets, we used Regressor Interpolation at Progressive Time Delays analyses to extract the sLFO from resting-state and task-based fMRI data. We evaluated relationships between sLFO amplitude and acute and chronic indices of nicotine use. We further assessed the effects of nicotine and methylphenidate on the sLFO and related task performance.

In individuals who smoked tobacco, higher average sLFO amplitude during cigarette cue exposure was negatively associated with nicotine dependence (n = 64; r = -0.32, p = .009), whereas a rise in the sLFO across the task was negatively associated with greater cue-induced craving (r = -0.31, p = .014). sLFO amplitude was reduced during chronic nicotine use versus abstinence (n = 65; p < .001). Relative to placebo, acute single-dose methylphenidate administration also reduced the sLFO in healthy control participants (n = 58; p = .001). Both acute methylphenidate- and nicotine-induced reductions in sLFO amplitude were associated with improved cognitive task performance.

These findings demonstrate that the sLFO encodes biologically meaningful information related to substance use, consistent with its role as an index of physiological arousal. Importantly, because the sLFO can be extracted directly from existing fMRI datasets, it offers a powerful and complementary approach to enhance the clinical relevance of fMRI research beyond substance use.