Developmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves

Abstract The cortex generates high-frequency oscillations (HFO) nested in slow waves during sleep, and these signals are especially elevated in the seizure onset zone. Thus, HFO occurrence rate and Modulation Index (MI), which quantifies the strength of coupling between HFO amplitude and slow-wave phase, represent promising epilepsy biomarkers. However, their diagnostic utility may be suboptimal because the endogenous developmental distributions are unknown. To improve age-appropriate localization of the epileptogenic zone, we hence constructed normative brain atlases demonstrating the developmental changes in MI and HFO rate. Our study investigated extraoperative, intracranial EEG data from 114 patients with focal epilepsy (ages 1.0 to 41.5 years) who achieved International League Against Epilepsy class I outcomes following resective surgery. We analyzed 20-minute slow-wave sleep epochs at 8,251 nonepileptic electrode sites (those outside the seizure onset zone, interictal spike zone, or MRI-visible lesions). Each electrode was transposed onto a standard brain template, and we then calculated its MI and HFO occurrence rate using four different detector toolboxes. Linear and nonlinear regression models determined the developmental slope of MI and HFO rate at each cortical mesh point. Mixed model analysis established the significance of MI and HFO rate developmental changes in each region of interest, while accounting for the independent effects of patient and epilepsy profiles. Finally, we created a dynamic tractography movie visualizing white matter pathways connecting cortical regions showing developmental co-growth in MI. We found that the occipital lobe exhibited enhanced MI compared to other lobes in both children and adults. Increased age, square root of age, and log base 10 of age were independently associated with elevated MI exclusively in the occipital lobe. The cortical regions showing developmental co-growth in MI were connected via the vertical occipital fasciculi and posterior callosal fibers. In contrast, we did not observe any significant association between age measures and HFO rate in the occipital lobe, but rather noted an inverse relationship between age and HFO rate in the temporal, frontal, and parietal lobes. Our study suggests that phase-amplitude coupling between physiologic HFO and delta waves, as rated by MI, is strengthened during development, in the occipital lobe particularly during toddlerhood and preschool. Given that occipital delta-nested HFO are believed to support visual memory consolidation, our observations imply that process may be significantly strengthened during early childhood. The data is publicly available to provide investigators with a crucial reference for MI and HFO-based presurgical evaluation of the epileptogenic zone.