Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception

Abstract

Conscious perception of painful stimuli needs the contribution of an extensive cortico-subcortical network, and is completed in less than one second. While initial activities in operculo-insular and mid-cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive-specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre-conscious activities were recorded in the posterior insula, operculum, mid-cingulate and amygdala. Antero-insular, prefrontal and posterior parietal activities started later and developed during time-frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino-thalamic and spino-parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto-parietal activity, while late-occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self-awareness and pain modulation. Hum Brain Mapp 37:4301-4315, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: consciousness; human; intracerebral EEG; nociceptive stimulus; pain matrix.

Figure 1

Laser evoked potentials recorded in the 16 studied areas. A: Responses obtained in posterior (n = 25) and anterior (n = 13) insulae, parietal (n = 8) and frontal (n = 8) operculi. B: Responses obtained in amygdala (n = 14) and hippocampus (n = 10). C: Responses obtained in cingulate cortices: pACC (n = 5), ACC (n = 4), MCC (n = 8), dPCC (n = 8), vPCC (n = 5). D: Responses obtained in OFC (n = 7), DLPFC (n = 13), SMA (n = 7), precuneus (n = 8)and PPC (n = 9). For each area Left: Recording contact locations in each area represented on MNI Brain templates; Right: Grand averages (+/‐ SEM) of responses obtained in each area (in referential and bipolar modes).

Figure 2

Onset latencies of the nociceptive responses recorded in the 14 areas analyzed (bipolar mode). A: Latency differences between the 13 areas, relative to that of the posterior insula. Two points of inflection clearly distinguish 3 groups: the first one with virtually no latency difference relative to the post‐insula comprising the parietal operculum, mid cingulate, SMA, and amygdala (latency difference around zero); the second group with a progressive but relatively small latency increase including the frontal operculum, anterior insula, precuneus, OFC, DLPFC, and the third group with a greater rate of latency increase including the posterior parietal cortex, posterior and perigenual cingulate, and hippocampus. B: Onset latencies (top) and grand‐averaged traces (bottom) of the three groups: the first one with a 110 − 130 ms onset latency range; the second with a 130 − 150 ms onset latency range and the third one with a 150 − 180 ms onset latency range. The small arrows point to the mean onset of the responses and the areas delineated with dotted lines correspond to time windows during which motor reaction occurred (RT).

Figure 3

A: Phase coherence level of EEG frequency bands between posterior insula and the 13 cortical structures calculated in the 100 − 400 ms, 400 − 700 ms, and 700 − 1,000 ms time windows following nociceptive stimuli. Ordinate: level of coherence from 0.2 to 0.5; abscissa: cortical structures (anterior insula, parietal operculum, pACC, MCC, SMA, frontal operculum, precuneus, PPC, amygdala, DLPFC, hippocampus, vPCC, OFC); third coordinate: frequency bands (δ, τ, α, β, γ). B: Mean levels of coherence between posterior insula and all other areas according to time window, showing the significant increase of this level during the second and third time window as compared to the first one. C: Mean levels of coherence between posterior insula and each of the other areas, showing highest values for the anterior insula, parietal operculum, and pACC as compared to the others.

Figure 4

Phase spectral coherences during the three time windows represented on normalized anatomical model of the brain proposed by the McConnell Brain Imaging Centre of the Montreal Neurological Institute. Coherences between posterior insula and 13 cortical areas: Left. Recording contact locations in the posterior insula represented on a sagittal slice. Top: Sagittal slice for anterior insula, amygdala and hippocampus; Mid: Brain convexity for posterior parietal cortex, parietal operculum, frontal operculum and dorso‐lateral prefrontal cortex; Bottom. Mid‐sagittal slice for precuneus, ventral posterior cingulate, SMA, mid cingulate, perigenual anterior cingulate and orbito‐frontal cortex. Levels of coherence during the three time windows are represented in each histogram. Ordinate: level of coherence from 0.1 to 0.4; abscissa: time windows (front: 100 − 400, middle: 400 − 700, back: 700 − 1,000 ms). Note that the coherence values between the insula and a large majority of other cortical areas increase with time.