Multimodal characterization of cortical amplitude of low-frequency fluctuation alterations in chronic low back pain:...

Chronic low back pain (CLBP) is associated with widespread disruptions in intrinsic brain activity; however, the underlying molecular and neurochemical mechanisms remain unclear. This study aimed to elucidate the multiscale biological substrates of alterations in spontaneous neural activity in CLBP using a multimodal framework.

We enrolled 41 patients with CLBP and 41 matched healthy controls. Resting-state functional MRI was utilized to assess the amplitude of low-frequency fluctuations (ALFFs), a marker of spontaneous brain activity. Regional alterations in ALFF were mapped and correlated with spatial gene expression profiles from the Allen Human Brain Atlas and neurotransmitter receptor density maps derived from PET.

Compared with healthy controls, patients with CLBP exhibited increased ALFF in the left cerebellar lobule 10 and decreased ALFF in five cortical regions spanning the visual, default mode, sensorimotor, and frontoparietal networks. Transcriptomic analysis revealed that ALFF-related genes were enriched in pathways associated with synaptic transmission and immune response and were predominantly expressed in excitatory and inhibitory neurons. Spatial correlations further indicated significant alignment between ALFF alterations and the regional distributions of μ-opioid, 5-HT1a serotonin, and CB1 cannabinoid receptors.

Our findings highlight a multiscale interplay among spontaneous brain activity, gene expression, and neuromodulatory systems in CLBP. Regionally specific alterations in ALFF reflect imbalances between neuronal excitation and neuroimmune regulation, constrained by the spatial architecture of neurotransmitter systems. These results enhance our understanding of the neurobiological basis of chronic pain and suggest potential targets for mechanism-informed interventions.