A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials

Abstract

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

Keywords: axonal conduction delay; cortico-cortical evoked potential; dynamic causal modelling; neural mass models; synaptic time constant.

Figure 1

Estimation of CCEPs neuronal parameters at the individual level. (A) Architecture of the generative model underlying the early N1 component of CCEPs. Each of the stimulation (red circle) and recording (blue circles) sites are modelled with local neural mass models. Following a transient bipolar stimulation and for a sufficient charge level (product of pulse intensity and duration), action potentials initiated in the stimulated region propagate via orthodromic projections to connected regions, where significant responses are recorded. (B) Model predictions (red) of CCEP observations (blue) for increasing N1 peak latencies (vertical line). Estimated axonal conduction delays (Ax), excitatory (Se) and inhibitory (Si) synaptic time constants are indicated on top of each panel. (C) Distribution of the estimated neuronal delays. The main panels (coloured 2D histograms) represent the joint distribution of the axonal conduction delays (left), excitatory (middle) and inhibitory (right) synaptic time constants (horizontal axes) according to the N1 peak latency (vertical axis). White colour indicates an absence of data. The side panels (grey 1D histograms) show the marginal distributions of the N1 peak latencies (vertical plot on the left) and of each neuronal parameter (horizontal plots at the bottom).

Figure 2

Estimation of axonal conduction delays between brain regions. Results are presented for the older group (>15 years) based on the Lausanne2008-60 parcellation scheme. The matrix presents median axonal delays for this group, between stimulating (vertical axis) and recording (horizontal axis) parcels based on the Lausanne2008-60 parcellation scheme. Grey-coloured entries indicate the absence of direct connections (or an insufficient number of significant responses fitted with accuracy).

Figure 3

Brain mapping of axonal conduction delays. Median axonal conduction delays are presented for the efferent connections from one stimulated parcel (pointed by a red arrow) to the rest of the brain. Here, the series of stimulated parcels have been chosen in the left hemisphere: (A) the pars triangularis, (B) the pars opercularis, (C) the superior temporal gyrus and (D) the amygdala. Results are presented for the older group (>15 years) based on the Lausanne2008-60 parcellation scheme.

Figure 4

Brain mapping of axonal conduction delays for the right insula. (A) Efferent connections: the insula is stimulated and CCEPs are recorded in other regions. (B) Afferent connectivity: insula is recording CCEPs when stimulation is performed in other regions. Results are presented for the older group (>15 years) based on the Lausanne2008-60 parcellation scheme. The red arrow indicates the right insula.

Figure 5

Estimation of conduction velocities. Results are presented for the older group (>15 years) based on the Lausanne2008-60 parcellation scheme. Distributions of (A) N1 peak latencies (median: 37.0 ms), (B) axonal conduction delays (median: 10.2 ms), and conduction velocities based on (C) N1 peak latencies (median: 1.1 m/s) and (D) axonal conduction delays (median: 3.9 m/s). Distances between stimulating and recording contacts were measured along white matter fibres, using the ARCHI DTI atlas (see ‘Group-level analysis’ section).

Figure 6

Estimation of synaptic time constants. Results are presented for the whole group based on the 360 parcels of the HCP-MMP1 parcellation scheme. (A) Distribution (left) and brain mapping (right) of excitatory synaptic time constants. (B) Distribution (left) and brain mapping (right) of inhibitory synaptic time constants. For a very few grey-coloured cortical regions, the estimation was not possible, due to an insufficient amount of data.