Effective connectivity of the insula as measured by cortico-cortical evoked potentials

Effective connectivity of the human insula, mainly assessed at rest using cortico-cortical evoked potentials (CCEPs), is not yet fully characterized at high-resolution. Here, we significantly extend prior CCEP studies of the insula by leveraging an extensive multicenter CCEP database and fine-grained anatomical atlases of the insula. We analyzed CCEP datasets from 897 patients with refractory focal epilepsy (459 females, age: 26±14 years) explored by stereo electroencephalography and with at least one electrode contact in the insula. Efferent and afferent effective connectivity measures of nineteen insular subregions with the rest of the brain were derived at the population level, by pooling statistical properties of early brain responses to electrical stimulation pulses, as defined by the first significant component of CCEPs occurring before 100 ms. In addition, the median peak delay of the responses was measured as a proxy of the directness of the connections. Results revealed predominant ipsilateral insular connections with frontal, parietal, central, temporal, and limbic systems. Some directional biases were observed, with more afferent connections from the caudal part of frontal lobe, central regions, temporoparietal junction, temporal pole and amygdala, and more efferent connections to the rostral part of frontal lobe, anterior cingulate, parahippocampal cortex, and hippocampus. Subregional analysis revealed a remarkably preserved topological pattern with a gradient of effective connectivity along anterior-posterior and superior-inferior axes. Along the anterior-posterior axis, the posterior insula demonstrated predominant connections with parietal, central, temporal, and limbic systems, while the anterior insula was additionally connected with the frontal system. Along the superior-inferior axis, superior insula was mainly connected with frontal, parietal, central, temporal, and limbic systems, whereas the inferior insula was primarily connected with temporal and limbic regions. Median peak delays range from 14 to 51 ms, with the fastest responses in insula surrounding areas. This study provides the highest-resolution effective connectivity mapping of the human insula from neurophysiological data. It complements well previous structural studies with additional dynamical and causal information, and definitely establishes the insula as a topologically organised hub connecting the different brain lobes.