Modulation of Posterior Insula Selectively Enhances Nociceptive Sensory Gating in Humans

Sensory gating - the brain's ability to filter out repetitive sensory input - is essential for preventing sensory overload. Impaired gating is frequently observed in nociplastic and other chronic overlapping pain conditions, yet the specific brain regions supporting this inhibitory process in humans remains unclear. Neuroimaging studies examining pain processing implicate the anterior insula (AI), posterior insula (PI), and anterior mid-cingulate cortex (aMCC), but their deeper locations limit direct mechanistic testing using conventional non-invasive techniques. Here, we leveraged low-intensity focused ultrasound (LIFU), a novel non-invasive neuromodulation method with high depth-penetration and millimeter resolution, to examine the contributions of the AI, PI, and aMCC to sensory gating of nociceptive stimuli. Twelve healthy adults completed four counterbalanced visits of a paired-pulse contact heat evoked potential (CHEP) paradigm while receiving LIFU targeted to each region or an active sham. Using surface electroencephalography (EEG), placed at site Cz, we quantified the peak-to-peak (P2P) amplitude of the cortical response to the first stimulus (S1), the second stimulus (S2), and used the ratio of the response to each stimulus (S2/S1 ratio) as an index of sensory gating. Subjective ratings of pain intensity to the second stimulus were also recorded. Results demonstrated that all subjects displayed sensory gating at baseline and thatLIFU produced region-specific effects. Both PI and aMCC neuromodulation reduced subjective pain ratings and significantly decreased S2 amplitude relative to sham, whereas LIFU to AI had no effect. Critically, only PI neuromodulation enhanced sensory gating by reducing the S2/S1 ratio. These findings identify the PI as a key contributor to gating of repetitive nociceptive input and a promising neuromodulation target for remediating sensory gating deficits in nociplastic pain.