Abstract

While nociceptive cortical activation is now well characterized in humans, understanding of the nociceptive thalamus remains largely fragmentary. We used laser stimuli and intracerebral electrodes in 17 human subjects to record nociceptive-specific field responses in 4 human thalamic nuclei and a number of cortical areas. Three nuclei known to receive spinothalamic (STT) projections in primates (ventro-postero-lateral [VPL], anterior pulvinar [PuA], and central lateral [CL]) exhibited responses with similar latency, indicating their parallel activation by nociceptive afferents. Phase coherence analysis, however, revealed major differences in their functional connectivity: while VPL and PuA drove a limited set of cortical targets, CL activities were synchronized with a large network including temporal, parietal, and frontal areas. Our data suggest that STT afferents reach simultaneously a set of lateral and medial thalamic regions unconstrained by traditional nuclear borders. The broad pattern of associated cortical networks suggests that a single nociceptive volley is able to trigger the sensory, cognitive, and emotional activities that underlie the complex pain experience. The medial pulvinar, an associative nucleus devoid of STT input, exhibited delayed responses suggesting its dependence on descending cortico-thalamic projections. Its widespread cortical connectivity suggests a role in synchronizing parietal, temporal, and frontal activities, hence contributing to the access of noxious input to conscious awareness.

Introduction

Neurofunctional studies in humans have provided convergent data on the main cortical structures activated by nociceptive stimuli (Peyron et al. 2000; Garcia-Larrea et al. 2003; Apkarian et al. 2005; Tracey and Mantyh 2007; Garcia-Larrea and Peyron 2013). In contrast, the functional characteristics of human thalamic responses to peripheral nociceptive activation (the “nociceptive thalamus”) have remained so far elusive and are still extensively debated (review, Lenz et al. 2010). Hemodynamic studies frequently show a broad thalamic activation to noxious peripheral input (Casey et al. 1994; Davis et al. 1998; Peyron et al. 2000; Apkarian et al. 2005; Garcia-Larrea and Peyron 2013), but their limited spatial resolution greatly restricts topographical analysis. Also, since electromagnetic fields linked to thalamic activities diminish sharply with distance due to their “closed field” properties (Lorente de Nó 1947), thalamic electroencephalography (EEG)/magnetoencephalography responses are hardly recordable from the scalp. Intrathalamic microelectrode recordings in humans have demonstrated neuronal responses to thermal—nociceptive stimuli within the thalamic somatosensory principal (ventro-postero-lateral, VPL) nucleus (Lenz, Seike, Lin et al. 1993; Kobayashi et al. 2009), as well as in regions posterior–inferior to it (Lee et al. 1999). However, the VPL nucleus “proper” (also labeled “ventrocaudal”, or Vc, nucleus) may be of limited importance in the processing of nociceptive-specific information, as its direct microstimulation in humans rarely evokes pain (Lenz, Seike, Richardson et al. 1993, 1995; Davis et al. 1996; Rezai et al. 1999), neurons responding to painful heat stimuli are scarce (Lenz, Seike, Lin et al. 1993), and nociceptive-specific input to VPL from superficial dorsal horn may not exceed 10–15% (Willis et al. 2001; Craig 2006).

In contrast with the dorsal column/medial lemniscal pathway that terminates in a restricted thalamic region (VPL/Vc), the thalamic terminus of the spinothalamic (STT) pathway in primates include extensive regions covering nuclei of the lateral, posterior, and medial thalamus (Mehler 1962, 1966; Rausell et al. 1992; Graziano and Jones 2004; Ralston 2005). Three main thalamic areas are concerned: 1) a relatively sparse projection to the principal somatosensory nuclei (VPL/VPM), 2) a more dense projection posterior, medial, and inferior to the latter, and (iii) a strong medial projection to parafascicularis, mediodorsal, and central lateral (CL) intralaminar nuclei (reviews, Lenz et al. 2010; Garcia-Larrea and Magnin 2013). To the best of our knowledge, no previous data in humans have been reported on the functional characteristics of thalamic activities within these different thalamic areas in response to nociceptive-specific input, nor on the functional relation between thalamic nuclei involved in nociception and the cortical regions supposedly receiving information from nociceptive systems. The opportunity to record, in epileptic patients implanted with intracerebral electrodes, nociceptive-specific responses simultaneously from different thalamic regions and an extensive array of cortical areas allowed us to address this issue.

Patients and Methods

Patients

Seventeen patients with refractory partial epilepsy were included (11 men, 6 women; mean age 30 years, range 19–50 years) (Table 1). To delineate the extent of the cortical epileptogenic area and to plan a tailored surgical treatment, depth EEG recording electrodes (diameter 0.8 mm; 5–15 recording contacts 2-mm long, intercontact interval 1.5 mm) were implanted according to the stereotactic technique of Talairach and Bancaud (1973). The decision to explore specific areas resulted from the observation during scalp video-EEG recordings of ictal manifestations suggesting the possibility of seizures propagating to, or originating from these regions (Guenot et al. 2001). This procedure aims at recording spontaneous seizures but also includes the functional mapping of potentially eloquent cortical areas using evoked potentials recordings and cortical electrical stimulation (for a description of the stimulation procedure see Ostrowsky et al. 2002; Mazzola et al. 2006). The thalamus, at or near the pulvinar region, was one of the targets of stereotactic implantation because, due to its reciprocal connections with temporal and parietal cortical areas, it may be involved in most of temporal and insular lobe seizures (Trojanowski and Jacobson 1975; Baleydier and Mauguiere 1985; Pons and Kaas 1985; Gutierrez et al. 2000; Qi et al. 2002; Rosenberg et al. 2006, 2009). Simultaneous exploration of the thalamus and neocortical areas was possible using a single multicontact electrode, so that thalamic exploration did not increase the risk of the procedure by adding one further electrode track specifically devoted to it. In agreement with French regulations relative to invasive investigations with direct individual benefit, patients were fully informed about electrode implantation, stereotactic EEG, evoked potential recordings, and cortical stimulation procedures used to localize the epileptogenic cortical areas and gave their consent. The laser stimulation paradigm was submitted to, and approved by, the local Ethics Committee (CCPPRB Léon Bérard-Lyon).

Table 1

Individual clinical, MRI, and SEEG data

Patient Gender/age Treatment MRI Seizure onset Number of electrodes 
P1 M/19 Carbamazepin 800
Valproate 500
Clobazam 10 
R fronto-orbital R fronto-orbital 11/R 
P2 F/23 Levetiracetam 2000
Lamotrigin 800 
L hippocampal atrophy L mesial temporal 11/L 
P3 F/37 Carbamazepin 600
Pregabalin 75 
Normal L mesial temporal 13/L 
P4 M/26 Carbamazepin 200
Lamotrigin 200
Pregabalin 75 
L hippocampal atrophy L mesial temporal 12/L 
P5 M/20  R hippocampal atrophy R mesial temporal 12/R 
P6 M/21 Topiramate 200
Oxcarbazepin 900
Lamotrigin 400 
R temporal dysplasia R temporal 11/R+3/L 
P7 M/39 Lamotrigin 200
Topiramate 200
Levetiracetam 1000
Lacosamide 100 
L hippocampal atrophy L mesial temporal 11/L 
P8 M/19 None Normal R mesial temporal 11/R 
P9 F/50 Lamotrigin 200
Zonisamide 100
Phenobarbital 100 
L hippocampal atrophy L temporal 10/R+6/L 
P10 M/32 Levetiracetam 1000
Oxcarbazepin 150 
L hippocampal atrophy L basal temporal 13/L+2/R 
P11 M/36 Levetiracetam 1000
Lacosamide 100 
L amygdala atrophy L basal temporal 12/L+2/R 
P12 M/37 Carbamazepin 400
Topiramate 200
Clobazam 5 
Normal L perisylvian 13/L 
P13 F/23 Carbamazepin 200
Lamotrigin
Gabapentin 
L hippocampal atrophy L temporo amygdala 12/L 
P14 M/34 Carbamazepin 200
Lamotrigin 
L hippocampal atrophy L mesial temporal and insula 11/L 
P15 M/33 Carbamazepin
Phenytoin 
R frontal dysplasia R frontal and insula 12/R 
P16 F/33 Phenobarbital 100
Topiramate 200 
R hippocampal atrophy R mesial temporal 11/R 
P17 F/40 Lamotrigin
Valproate
Levetiracetam 
Parietal malformation L post parietal 13/L 
Patient Gender/age Treatment MRI Seizure onset Number of electrodes 
P1 M/19 Carbamazepin 800
Valproate 500
Clobazam 10 
R fronto-orbital R fronto-orbital 11/R 
P2 F/23 Levetiracetam 2000
Lamotrigin 800 
L hippocampal atrophy L mesial temporal 11/L 
P3 F/37 Carbamazepin 600
Pregabalin 75 
Normal L mesial temporal 13/L 
P4 M/26 Carbamazepin 200
Lamotrigin 200
Pregabalin 75 
L hippocampal atrophy L mesial temporal 12/L 
P5 M/20  R hippocampal atrophy R mesial temporal 12/R 
P6 M/21 Topiramate 200
Oxcarbazepin 900
Lamotrigin 400 
R temporal dysplasia R temporal 11/R+3/L 
P7 M/39 Lamotrigin 200
Topiramate 200
Levetiracetam 1000
Lacosamide 100 
L hippocampal atrophy L mesial temporal 11/L 
P8 M/19 None Normal R mesial temporal 11/R 
P9 F/50 Lamotrigin 200
Zonisamide 100
Phenobarbital 100 
L hippocampal atrophy L temporal 10/R+6/L 
P10 M/32 Levetiracetam 1000
Oxcarbazepin 150 
L hippocampal atrophy L basal temporal 13/L+2/R 
P11 M/36 Levetiracetam 1000
Lacosamide 100 
L amygdala atrophy L basal temporal 12/L+2/R 
P12 M/37 Carbamazepin 400
Topiramate 200
Clobazam 5 
Normal L perisylvian 13/L 
P13 F/23 Carbamazepin 200
Lamotrigin
Gabapentin 
L hippocampal atrophy L temporo amygdala 12/L 
P14 M/34 Carbamazepin 200
Lamotrigin 
L hippocampal atrophy L mesial temporal and insula 11/L 
P15 M/33 Carbamazepin
Phenytoin 
R frontal dysplasia R frontal and insula 12/R 
P16 F/33 Phenobarbital 100
Topiramate 200 
R hippocampal atrophy R mesial temporal 11/R 
P17 F/40 Lamotrigin
Valproate
Levetiracetam 
Parietal malformation L post parietal 13/L 

STT-specific laser stimulation was performed after a minimal delay of 5 days post electrode implantation; antiepileptic drugs had been tapered down with daily dosages at, or slightly under, the minimum of their usual therapeutic range (Table 1). None of these patients reported pain symptoms before or after the recording session.

Electrode Implantation

Intracerebral electrodes were implanted using Talairach's stereotactic frame. A cerebral angiography was performed in stereotactic conditions using an X-ray source located 4.85 m away from the patient's head. This eliminates the linear enlargement due to X-ray divergence, so that the films could be used for measurements without any correction. In a second step, the relevant targets were identified on the patient's MRI, previously enlarged to a scale of one-to-one. As MR and angiographic images were at the same scale, they could easily be superimposed, so as to avoid larger vessels and minimize the risk of hemorrhage during electrode implantation.

Anatomical Localization of Electrode Contacts

The localization of the contacts was determined using 2 different procedures. In 8 patients implanted before 2010, MRI could not be performed with electrodes in place because of the physical characteristics of the stainless steel contacts. In these cases, the scale 1:1 post implantation skull radiographs performed within the stereotactic frame of Talairach and Tournoux (1988) were superimposed to the preimplantation scale 1:1 MRI slice corresponding to each electrode track, thus permitting to plot each contact onto the appropriate MRI slice of each patient and determining its coordinates [MRIcroVR software; Rorden and Brett 2000]. In the other 9 patients, the implanted electrodes were MRI compatible and both thalamic and cortical contacts could be directly visualized on the postoperative 3D MRIs. In both cases, anatomical scans were acquired on a 3-Tesla Siemens Avanto Scanner using a 3D MPRAGE sequence with following parameters: TI/TR/TE 1100/2040/2.95 ms, voxel size: 1 × 1 × 1 mm3, FOV = 256 × 256 mm2.

Intrathalamic Electrode Contacts

The localization of the contacts within the thalamic nuclei was performed with the appropriate MRI slice of each patient and the Morel's stereotactic atlas of the human thalamus (Morel et al. 1997; Fig. 1). In the 9 patients with MRI-compatible electrodes, contacts could be localized according to their positions with respect to the anatomy in each patient, and then projected to the thalamic atlas. In the 8 patients without MRI-compatible electrodes, the coordinates of contacts were determined on their own MRI according to the procedure described above. In these cases, even after correction for contact locations and evaluation on individual patient's MRI, the contact localization is prone to inaccuracies linked to MRI slice thickness (±0.5 mm), superimposition of MRI slice on X-ray (±1 mm), and coordinates measurement (±0.5 mm), which leads to an average error (square root of the sum of the squares of the different errors) of ±1.32 mm in anteroposterior and dorsoventral dimensions, and ±1.11 mm in the mediolateral dimension (Rosenberg et al. 2006). We therefore checked in each patient that, even accounting for these possible errors, none of thalamic contacts could be located outside the thalamic nucleus considered. The coordinates of PuA contacts were 1–3 mm above AC-PC, 2–3 mm rostral to PC, and 11–15 mm lateral to AC-PC; those of VPL were 0–8 mm above AC-PC, 2–5 mm rostral to PC, and 15–19 mm lateral; those of CL were 6–10 mm above AC-PC, 1–5 mm rostral to PC, and 7–12 mm lateral; those of medial pulvinar (PuM) were 5–10 mm above AC-PC, +2 (rostral) to PC to −7 (caudal) to PC, and 13–19 mm lateral to the midline. Note that, although the PuM is adjacent to VPL in its most ventral sections, it becomes contiguous to the CL at the z-axis levels explored in this study (>5 mm above AC-PC).

Figure 1.

Characteristics of the nociceptive responses in the 4 thalamic nuclei recorded. (A) Horizontal section of the stereotactic Morel's atlas (1997) 4.5 mm above AC/PC showing the 4 thalamic nuclei. (B) Grand averages (±SEM) of responses obtained in each nucleus. The arrows indicate the onset and peak of the responses. (C) Enlargements of horizontal sections of the stereotactic Morel's atlas (1997) focused on each nucleus show the contact localizations at which responses were recorded in each patient. Contacts in the left thalamus were X-flipped to the right one. (D) Graphs showing for each nucleus the mean latencies (±SEM) of onset and peak of the first response component and its slope (amplitude/duration from onset to peak). Note that response onset in PuM is significantly delayed when compared with those recorded in the 3 other nuclei and that the slope of the PuA response is steeper when compared with the others.

Figure 1.

Characteristics of the nociceptive responses in the 4 thalamic nuclei recorded. (A) Horizontal section of the stereotactic Morel's atlas (1997) 4.5 mm above AC/PC showing the 4 thalamic nuclei. (B) Grand averages (±SEM) of responses obtained in each nucleus. The arrows indicate the onset and peak of the responses. (C) Enlargements of horizontal sections of the stereotactic Morel's atlas (1997) focused on each nucleus show the contact localizations at which responses were recorded in each patient. Contacts in the left thalamus were X-flipped to the right one. (D) Graphs showing for each nucleus the mean latencies (±SEM) of onset and peak of the first response component and its slope (amplitude/duration from onset to peak). Note that response onset in PuM is significantly delayed when compared with those recorded in the 3 other nuclei and that the slope of the PuA response is steeper when compared with the others.

Intracortical Electrode Contacts

Intracortical electrode contacts were mapped to the standard stereotaxic space (Montreal Neurological Institute, MNI) by processing MRI data with Statistical Parametric Mapping (SPM12—Wellcome Department of Cognitive Neurology, UK; http:// www.fil.ion.ucl.ac.uk/spm/). Anatomical T1-3D images pre- and postimplantation were co-registered and normalized to the MNI template brain image using a mutual information approach (Maes et al. 1997), and the segmentation module of SPM12, which segments, corrects bias and spatially normalizes images with respect to the MNI model (Ashburner and Friston 2005). Then, the cortical localization of electrodes was performed using regional atlas in MRIcro®. In the 9 patients with MRI-compatible electrodes, the cortical contacts could be directly visualized on the postoperative normalized 3D MRIs. In the 8 patients without MRI-compatible electrodes, the coordinates of contacts were determined on their own MRI according to the procedure described above, thus permitting to plot each contact onto the appropriate MRI slice of each patient [MRIcron software; Rorden and Brett 2000] and determining its MNI coordinates.

Nociceptive-Specific Laser Stimulation

Radiant nociceptive heat pulses of 5-ms duration were delivered with a Nd:YAP laser (Yttrium Aluminium Perovskite; wavelength 1.34 µm; El.En.®, Florence, Italy). The laser beam was transmitted from the generator to the stimulating probe via an optical fiber of 10 m length (550 µm diameter with sub miniature version A-905 connector). Before the recording session, nociceptive thresholds were determined as the minimal laser energy producing a pricking sensation, compared with pulling a hair or receiving a boiling water drop in at least 2 of 3 stimuli. They were obtained in all subjects with energy densities between 60 and 100 mJ/mm2, which are within the usual data range observed in our laboratory and those reported by others using Nd:YAP lasers (Cruccu et al. 2008); these parameters have been validated as being able to activate selectively the STT system in humans (Garcia-Larrea et al. 2010; Perchet et al. 2012).

Data Acquisition and Recording Procedure

In each patient, 2 runs of 10–15 stimulations each, at nociceptive threshold, were applied to the skin in the superficial radial nerve territory on the dorsum of the hand contralateral to the hemispheric side of electrodes implantation. The heat spot was slightly shifted over the skin surface between 2 successive stimuli to avoid both sensitization and peripheral nociceptor fatigue. Seven patients were stimulated on the right hand, and 10 on the left hand. Recordings were performed on referential mode, the reference electrode being chosen for each patient on an implanted contact located in the skull. EEG was recorded continuously at a sampling frequency of 256 Hz from 96 to 128 channels, amplified, and band pass filtered (0.33–128 Hz; −3 dB, 12 dB/octave) to be stored in hard disk for offline analysis (Micromed SAS®, Macon, France).

Electrophysiological Data Analyses

Laser-Evoked Potentials

The coordinates of the thalamic contacts exhibiting the largest responses to laser stimuli are indicated on Table 2. Epoching of the EEG, selective averaging, and recordings analysis were performed offline using BrainVision® System (Brain Products®, Munich, Germany). Epochs contaminated by epileptic transient activities or artifacts exceeding 100 µV were rejected from analysis, leading to a rejection rate of 10%. Laser-evoked potentials (LEP) components recorded in the thalamus were assessed using both monopolar (referential) and bipolar montages, within a time window of 100-ms prestimulus and 900-ms poststimulus. Were measured in each patient: 1) the onset and peak latencies of the LEP first component, 2) the amplitudes of the first (from onset to peak) and of the second LEP components (from peak to peak), and 3) the slope of the first component, obtained by dividing its amplitude by its duration from onset to peak. The onset latencies were defined at the time when amplitude values differed by 2 standard deviations from those of mean baseline. Statistical analyses were performed with GraphPad Prism 6 and StatView® softwares. Latencies, durations, amplitudes, and slopes were submitted to one-way ANOVA, with significance level set at P < 0.05 (Greenhouse–Geisser corrected if needed). When the mean value of any variable from one single nucleus differed by more than one standard deviation (SD) from the others, predefined contrasts were tested between this and the other nuclei.

Table 2

Coordinates of thalamic contacts referred to AC-PC

Contacts VPL (N = 5)
 
PuA (N = 3)
 
CL (N = 4)
 
PuM (N = 10)
 
Patients X Y Z X Y Z X Y Z X Y Z 
P1          19 −3 
P2          17 −7 
P3       17 
P4          
P5 18 11       
P6       12 10    
P7 19 15       
P8 17    10    
P9 15          
P10          19 −1 
P11          16 
P12          13 −1 
P13          14 −7 10 
P14          18 −2 
P15          18 
P16          15 10 
P17 15 12       
Mean 17 12.7 2.7 2.3 7.8 16.6 −1.7 7.3 
SD 1.6 1.2 3.1 2.1 0.6 1.2 2.5 1.6 1.7 2.1 3.2 1.8 
Contacts VPL (N = 5)
 
PuA (N = 3)
 
CL (N = 4)
 
PuM (N = 10)
 
Patients X Y Z X Y Z X Y Z X Y Z 
P1          19 −3 
P2          17 −7 
P3       17 
P4          
P5 18 11       
P6       12 10    
P7 19 15       
P8 17    10    
P9 15          
P10          19 −1 
P11          16 
P12          13 −1 
P13          14 −7 10 
P14          18 −2 
P15          18 
P16          15 10 
P17 15 12       
Mean 17 12.7 2.7 2.3 7.8 16.6 −1.7 7.3 
SD 1.6 1.2 3.1 2.1 0.6 1.2 2.5 1.6 1.7 2.1 3.2 1.8 

Thalamo-Cortical Coherence

EEG phase coherence between the 4 thalamic nuclei and cortical structures was calculated during 2 time windows, one between 100 and 400 ms and the other between 400 and 700 ms following each nociceptive stimulus. The coordinates of the cortical areas used for EEG coherence analysis are indicated in Table 3. Coherence was computed after Fast Fourier transform of the signal for each spectral band power (δ: 1–3 Hz, θ: 4–7 Hz, α: 8–12 Hz, β: 13–29 Hz, γ: 30–64 Hz) with a resolution of 1 Hz. The phase coherence between each pair of electrode contacts was calculated using the quotient between cross-spectral and auto spectral density functions for each frequency and each channel. Fisher's z-transformation was applied to coherence data before statistical analyses. In order to avoid too many comparisons, coherence values were grouped as “low frequency” (δ + θ-bands, 1–7 Hz), “middle frequency” (α + β-bands, 8–24 Hz), and “high frequency” (γ-band, 25–64 Hz). To determine whether a given level of coherence between 2 regions was above noise, its statistical significance was estimated by contrasting with random levels of coherence, obtained from thalamo-cortical recordings in which the amplitude levels of one of the time series was randomly reordered (e.g., Miranda de Sá et al. 2002). The resulting “random” spectra showed average coherence levels of 0.042 ± 0.046 for δ + θ, 0.055 ± 0.045 for α + β, and 0.038 ± 0.047 for γ. Therefore, coherence levels ≥0.2 (i.e., 3 SDs above mean random coherence levels) were considered significantly different from noise. This level was consistent with previous studies of intracortical or scalp activity using similar recording parameters (Achermann and Borbély 1998; Cantero et al. 2004). Mean coherence values between the different cortical areas and each thalamic nucleus were then calculated and submitted to a three-way mixed ANOVA with frequency bands and time as within factors and thalamic nuclei as between factor. Post hoc tests were applied in case of significant effects following ANOVA.

Table 3

MNI coordinates of cortical contacts

Contacts BA 46 (N = 7)
 
BA 10-11 (N = 7)
 
BA 24 (N = 6)
 
A insula (N = 9)
 
Amygd (N = 12)
 
Patients X Y Z X Y Z X Y Z X Y Z X Y Z 
P1 41 34 21 41 −13 34 21    16 −5 −17 
P2             15 −5 −21 
P3 27 40 20 45 −17 21 23 27 14    
P4 30 42 13    42 −4 28    
P5 32 46 11 34 −14    27 11 12 15 −4 −19 
P6          34 −9 21    
P7 52 41 19 61       11 −8 −28 
P8 51 37 21    43 20 29 14 24 −19 
P9             18 −3 −18 
P10       35    18 −16 
P11    15 43 −15       25 −3 −23 
P12 41 46 17 49 −4    29 25 −1 −17 
P13          32 13 18 −10 −12 
P14          31 −1    
P15       37 32 14 17 −1 −17 
P16    10 43 −7       18 −1 −20 
P17                
Mean 39 41 17 45 −9 35 12 30 11 18 −3 −19 
SD 10 11 
Contacts Hippo (N = 16)
 
P insula (N = 17)
 
BA 40 (N = 11)
 
BA 7 (N = 9)
 
BA 23 (N = 10)
 
Patients X Y Z X Y Z X Y Z X Y Z X Y Z 
P1 24 −13 −23 36 −28 57 −54 41 11 −54 41 −55 17 
P2 22 −27 −12 30 −29 41 −54 34 27 −54 34 16 −48 20 
P3 23 −16 −19 32 −22 34 −55 36 13 −55 36 −48 14 
P4 21 −17 −21 31 −24          
P5 24 −16 −14 36 −22 34 −48 36 −48 36    
P6 22 −19 −15 35 −23 10 37 −33 52 14 −33 52 −59 23 
P7 34 −27 −6 37 −21 47 −55 43 13 −60 43 14 −47 25 
P8 28 −14 −20 34 −20          
P9 22 −16 −20 35 −8 −10          
P10 29 −20 −16 34 −14 39 −46 31    15 −65 21 
P11 26 −15 −16 40 −5 −3 48 −45 26    14 −46 27 
P12 27 −16 −11 35 −13          
P13 23 −24 −10 29 −32 10 39 −31 34 11 −31 34    
P14 23 −15 −25 35 −19 −5       −42 18 
P15    30 −4 18 40 −31 61 −31 61 −27 29 
P16 23 −15 −18 32 −11 −2          
P17 24 −14 −19 35 −4 32 −50 44 −40 44 −46 18 
Mean 25 −18 −17 34 −17 41 −46 40 12 −45 42 10 −48 21 
SD 10 10 11 10 
Contacts BA 46 (N = 7)
 
BA 10-11 (N = 7)
 
BA 24 (N = 6)
 
A insula (N = 9)
 
Amygd (N = 12)
 
Patients X Y Z X Y Z X Y Z X Y Z X Y Z 
P1 41 34 21 41 −13 34 21    16 −5 −17 
P2             15 −5 −21 
P3 27 40 20 45 −17 21 23 27 14    
P4 30 42 13    42 −4 28    
P5 32 46 11 34 −14    27 11 12 15 −4 −19 
P6          34 −9 21    
P7 52 41 19 61       11 −8 −28 
P8 51 37 21    43 20 29 14 24 −19 
P9             18 −3 −18 
P10       35    18 −16 
P11    15 43 −15       25 −3 −23 
P12 41 46 17 49 −4    29 25 −1 −17 
P13          32 13 18 −10 −12 
P14          31 −1    
P15       37 32 14 17 −1 −17 
P16    10 43 −7       18 −1 −20 
P17                
Mean 39 41 17 45 −9 35 12 30 11 18 −3 −19 
SD 10 11 
Contacts Hippo (N = 16)
 
P insula (N = 17)
 
BA 40 (N = 11)
 
BA 7 (N = 9)
 
BA 23 (N = 10)
 
Patients X Y Z X Y Z X Y Z X Y Z X Y Z 
P1 24 −13 −23 36 −28 57 −54 41 11 −54 41 −55 17 
P2 22 −27 −12 30 −29 41 −54 34 27 −54 34 16 −48 20 
P3 23 −16 −19 32 −22 34 −55 36 13 −55 36 −48 14 
P4 21 −17 −21 31 −24          
P5 24 −16 −14 36 −22 34 −48 36 −48 36    
P6 22 −19 −15 35 −23 10 37 −33 52 14 −33 52 −59 23 
P7 34 −27 −6 37 −21 47 −55 43 13 −60 43 14 −47 25 
P8 28 −14 −20 34 −20          
P9 22 −16 −20 35 −8 −10          
P10 29 −20 −16 34 −14 39 −46 31    15 −65 21 
P11 26 −15 −16 40 −5 −3 48 −45 26    14 −46 27 
P12 27 −16 −11 35 −13          
P13 23 −24 −10 29 −32 10 39 −31 34 11 −31 34    
P14 23 −15 −25 35 −19 −5       −42 18 
P15    30 −4 18 40 −31 61 −31 61 −27 29 
P16 23 −15 −18 32 −11 −2          
P17 24 −14 −19 35 −4 32 −50 44 −40 44 −46 18 
Mean 25 −18 −17 34 −17 41 −46 40 12 −45 42 10 −48 21 
SD 10 10 11 10 

Results

Grand averages of thalamic nociceptive responses are illustrated in Figure 1. Local responses to laser heat pulses were recorded in the VPL (110 responses), the CL nucleus (88 responses), the PuA (58 responses), and the PuM (173 responses). Onset response latencies differed significantly across the 4 nuclei (F3,18 = 28.95; P < 0.0001), the onset latency of the PuM (237.6 ± 11.9 ms) being significantly longer than those of the 3 other thalamic nuclei (contrast F1,3 = 84.54; P < 0.0001) which in turn did not differ among them (Fig. 1, bottom) (VPL: 122.6 ± 5.4 ms; CL: 129 ± 8.1 ms; PuA: 126.3 ± 2.7 ms). Peak latencies were also significantly different across nuclei (F3,18 = 32.79; P < 0.0001), explained by a longer peak latency in PuM (391.5 ± 19.1 ms) when compared with the other 3 nuclei (contrast F1, 3 = 95.11; P < 0.001) which did not differ from each other (VPL: 184.2 ± 7.9 ms; CL: 214.8 ± 19.5 ms; PuA: 187.3 ± 7.7 ms).

Significant differences in peak-to-peak amplitudes (F3,18 = 3.61; P = 0.034) were explained by much higher amplitude values in PuA than in the other nuclei (PuA: 79.7 ± 46 µV; VPL: 32.5 ± 14.5 µV; CL: 42.9 ± 21.4 µV; PuM: 28.9 ± 9.1 µV; contrast F1,3 = 8.86; P = 0.008). While the differences in onset-to-peak amplitudes across the 4 nuclei did not reach significance, their respective “slopes” did (F3,18 = 3.95; P = 0.025), being again higher in PuA than in the other nuclei (PuA: 58 ± 15 µV/ms) VPL: 28 ± 6 µV/ms; CL: 33 ± 10 µV/ms; PuM: 21 ± 4 µV/ms; contrast F1,3 = 8.72; P = 0.0085).

Figure 2 illustrates representative thalamic responses in 4 patients. PuA and VPL exhibited similar response shape, with a main negative–positive component, although its amplitude and steepness were much larger in the PuA (Figs 1 and 2). Polarity reversals indicating a local response origin were recorded at the boundaries between CL/VPL and VPL/thalamic reticular nucleus (Fig. 2B). Since only one contact per patient could be strictly localized within the PuA, no phase reversals were recorded, the response specificity being supported by its sharp decrease in adjacent contacts outside the nucleus (66% amplitude drop in/out PuA; Fig. 2C). Similarly, a drastic amplitude decrease (>80%) was observed between contacts within the PuM and those lying immediately outside this nucleus (Fig. 2D).

Figure 2.

Thalamic evoked responses to nociceptive laser stimuli obtained in 4 patients. Horizontal preimplantation MR images are centered on the stereotactic dorsoventral coordinate corresponding to electrode positions. The localization of the different contacts, determined on postimplantation MR images, is numbered from medial to lateral. The corresponding planes of Morel's atlas (1997) are superimposed on MR images in each patient. LEP recorded from the different contacts are shown in referential mode. (A) LEP recorded in PuA and VPL (20 stimuli). Note the significantly larger amplitude of the averaged PuA response. (B) LEP recorded in CL and VPL (30 stimuli). A polarity reversal is observed between contacts 3–4 supporting local origin within VPL. A second aspect of polarity reversal is also observed between contacts 1–2, but its meaning is difficult to ascertain since contact 2 appears to overlap CL, VPL, and LP nuclei, its response being probably dominated by the VPL response. Note the difference in LEP morphology between responses recorded in these 2 thalamic nuclei. (C) LEP recorded in PuA and VPL (25 stimuli). Note the difference in amplitudes between the 2 nuclei. (D) LEP recorded in PuM (15 stimuli). Note the delayed response in PuM compared with LEPs recorded in the 3 other thalamic nuclei.

Figure 2.

Thalamic evoked responses to nociceptive laser stimuli obtained in 4 patients. Horizontal preimplantation MR images are centered on the stereotactic dorsoventral coordinate corresponding to electrode positions. The localization of the different contacts, determined on postimplantation MR images, is numbered from medial to lateral. The corresponding planes of Morel's atlas (1997) are superimposed on MR images in each patient. LEP recorded from the different contacts are shown in referential mode. (A) LEP recorded in PuA and VPL (20 stimuli). Note the significantly larger amplitude of the averaged PuA response. (B) LEP recorded in CL and VPL (30 stimuli). A polarity reversal is observed between contacts 3–4 supporting local origin within VPL. A second aspect of polarity reversal is also observed between contacts 1–2, but its meaning is difficult to ascertain since contact 2 appears to overlap CL, VPL, and LP nuclei, its response being probably dominated by the VPL response. Note the difference in LEP morphology between responses recorded in these 2 thalamic nuclei. (C) LEP recorded in PuA and VPL (25 stimuli). Note the difference in amplitudes between the 2 nuclei. (D) LEP recorded in PuM (15 stimuli). Note the delayed response in PuM compared with LEPs recorded in the 3 other thalamic nuclei.

Spectral coherence analysis was conducted between each of the 4 thalamic nuclei and the 10 cortical areas recorded concomitantly (posterior and inferior parietal [BA 7, BA 40], posterior and anterior cingulate [BA 23, BA 24], dorsolateral and ventromedial prefrontal cortices [BA 46, BA 10-11], anterior and posterior insula, hippocampus, and amygdala). PuA and VPL showed significant (Coh >0.2) levels of coherence with a relatively restricted network comprising the insula, posterior cingulate, hippocampus, amygdala, and BA 40 (SI/II not sampled) whatever the time window (Fig. 3). The pattern of thalamo-cortical coherence from CL and PuM was more extended and involved, in addition to the above cortical structures, the prefrontal, posterior parietal and anterior and posterior cingulate areas and this for the 2 time windows (Figs 3 and 4). ANOVA on mean coherence values showed a significant effect of thalamic nuclei [F3,30 = 7.86; P = 0.0005], and time window [F1,30 = 4.68; P = 0.0386] without any effect of frequency bands [F2,60 = 1.05; P = 0.343]; there were also 3 significant interactions, one between time and thalamic nuclei [F1,3,30 = 4.64; P = 0.0088], the second between frequency bands and thalamic nuclei [F2,60 = 5.77; P = 0.0004], and the third between time, frequency bands, and thalamic nuclei [F6,60 = 4.53; P < 0.0061]. Mean coherence values for CL and PuM were significantly larger than for VPL and PuA (contrast F1,2 = 21.60; P = 0.0001), and the mean coherence values of CL were significantly higher in the second when compared with the first time window (t = 2.47; P = 0.0388). Within the γ frequency band, coherence values of PuM were significantly larger than those of the CL (t = 2.35; P = 0.03) and of the VPL (t = 2.70; P = 0.015) (Fig. 5).

Figure 3.

Cortical functional coherence with respect to VPL and PuA. Left: Coherence level of EEG frequency bands calculated in the 100–400 and 400–700 ms time windows following nociceptive stimuli between each of the 2 thalamic nuclei and 10 different cortical structures. VPL: ventral posterior lateral nucleus; PuA: anterior pulvinar. Ordinate: level of coherence from 0.1 to 0.6; abscissa: cortical structures (BA 46: dorsolateral prefrontal; BA 40: lateral parietal; A. insula: anterior insula; P. insula: posterior insula; Amygd: amygdala; Hippo: hippocampus; BA 11-10: orbito-frontal and prefrontal; BA 24: anterior cingulate; BA 23: posterior cingulate; BA 7: precuneus; third coordinate: frequency bands (δ + τ, α + β, γ). White parts on the histogram floor correspond to cortical structures where coherence values were not available. Right: Brain areas with significant level of coherence on normalized anatomical model of the brain proposed by the McConnell Brain Imaging Center of the Montréal Neurological Institute: (A) brain convexity showing lateral areas, (B) sagittal slices showing insula, projection of amygdale and hippocampus, and (C) mid-sagittal showing medial structures. Significant levels of coherence (>0.2) are represented for each structure with a color scale from yellow to red. Gray areas defined by dotted lines indicate that the level of coherence was <0.2, while the symbol “?” indicates that data in the area were not available.

Figure 3.

Cortical functional coherence with respect to VPL and PuA. Left: Coherence level of EEG frequency bands calculated in the 100–400 and 400–700 ms time windows following nociceptive stimuli between each of the 2 thalamic nuclei and 10 different cortical structures. VPL: ventral posterior lateral nucleus; PuA: anterior pulvinar. Ordinate: level of coherence from 0.1 to 0.6; abscissa: cortical structures (BA 46: dorsolateral prefrontal; BA 40: lateral parietal; A. insula: anterior insula; P. insula: posterior insula; Amygd: amygdala; Hippo: hippocampus; BA 11-10: orbito-frontal and prefrontal; BA 24: anterior cingulate; BA 23: posterior cingulate; BA 7: precuneus; third coordinate: frequency bands (δ + τ, α + β, γ). White parts on the histogram floor correspond to cortical structures where coherence values were not available. Right: Brain areas with significant level of coherence on normalized anatomical model of the brain proposed by the McConnell Brain Imaging Center of the Montréal Neurological Institute: (A) brain convexity showing lateral areas, (B) sagittal slices showing insula, projection of amygdale and hippocampus, and (C) mid-sagittal showing medial structures. Significant levels of coherence (>0.2) are represented for each structure with a color scale from yellow to red. Gray areas defined by dotted lines indicate that the level of coherence was <0.2, while the symbol “?” indicates that data in the area were not available.

Figure 4.

Cortical functional coherence with respect to CL and PuM. Left: Coherence level of EEG frequency bands calculated in the 100–400 and 400–700 ms time windows following nociceptive stimuli between each of the 4 thalamic nuclei and 10 different cortical structures. PuM: medial pulvinar; CL: central lateral nucleus. Ordinate: level of coherence from 0.1 to 0.6; abscissa: cortical structures (see Fig. 3); third coordinate: frequency bands (δ + τ, α + β, γ). White parts on the histogram floor correspond to cortical structures where coherence values were not available. Right: Brain areas with significant level of coherence on normalized anatomical model of the brain proposed by the McConnell Brain Imaging Center of the Montréal Neurological Institute: (A) Brain convexity showing lateral areas, (B) sagittal slices showing insula, projection of amygdale and hippocampus, and (C) mid-sagittal showing medial structures. Significant levels of coherence (>0.2) are represented for each structure with a color scale from yellow to red. Gray areas defined by dotted lines indicate that the level of coherence was <0.2, while the symbol “?” indicates that data in the area were not available.

Figure 4.

Cortical functional coherence with respect to CL and PuM. Left: Coherence level of EEG frequency bands calculated in the 100–400 and 400–700 ms time windows following nociceptive stimuli between each of the 4 thalamic nuclei and 10 different cortical structures. PuM: medial pulvinar; CL: central lateral nucleus. Ordinate: level of coherence from 0.1 to 0.6; abscissa: cortical structures (see Fig. 3); third coordinate: frequency bands (δ + τ, α + β, γ). White parts on the histogram floor correspond to cortical structures where coherence values were not available. Right: Brain areas with significant level of coherence on normalized anatomical model of the brain proposed by the McConnell Brain Imaging Center of the Montréal Neurological Institute: (A) Brain convexity showing lateral areas, (B) sagittal slices showing insula, projection of amygdale and hippocampus, and (C) mid-sagittal showing medial structures. Significant levels of coherence (>0.2) are represented for each structure with a color scale from yellow to red. Gray areas defined by dotted lines indicate that the level of coherence was <0.2, while the symbol “?” indicates that data in the area were not available.

Figure 5.

Thalamo-cortical functional coherence. (A) Left: Horizontal sections of the stereotactic Morel's atlas (1997) 7.2 above AC/PC showing CL and PuM. Right: Horizontal sections of the stereotactic Morel's atlas (1997) 2.7 mm above AC/PC showing VPL and PuA. Middle: Mean levels of coherence between the 4 thalamic nuclei and related cortical areas. Note the much higher thalamo-cortical coherence values for CL and PuM, relative to VPL and PuA (see text for statistics). (B). Mean levels of coherence between the 4 thalamic nuclei and related cortical areas according to time window. Note that the coherence value of CL was higher during the second time window when compared with the first one. (C) Interaction between frequency bands and thalamic nuclei. The mean coherence values were higher for CL and PuM than for VPL and PuA in the δ + τ and α + β, while in the γ band the PuM values were higher for PuM than CL and VPL and not than PuA.

Figure 5.

Thalamo-cortical functional coherence. (A) Left: Horizontal sections of the stereotactic Morel's atlas (1997) 7.2 above AC/PC showing CL and PuM. Right: Horizontal sections of the stereotactic Morel's atlas (1997) 2.7 mm above AC/PC showing VPL and PuA. Middle: Mean levels of coherence between the 4 thalamic nuclei and related cortical areas. Note the much higher thalamo-cortical coherence values for CL and PuM, relative to VPL and PuA (see text for statistics). (B). Mean levels of coherence between the 4 thalamic nuclei and related cortical areas according to time window. Note that the coherence value of CL was higher during the second time window when compared with the first one. (C) Interaction between frequency bands and thalamic nuclei. The mean coherence values were higher for CL and PuM than for VPL and PuA in the δ + τ and α + β, while in the γ band the PuM values were higher for PuM than CL and VPL and not than PuA.

Discussion

To the best of our knowledge, this is the first time that simultaneous data collected from such a diversity of thalamic and cortical areas in response to nociceptive-specific activation have been gathered in humans. Nuclei pertaining to lateral, posterior, or medial thalamic groups responded with similar latencies to STT input. Despite similar responding latencies, however, their patterns of cortical connectivity greatly differed. The largest nociceptive responses in the 4 nuclei explored came from the PuA despite its relatively small size, and the PuM, devoid of direct STT afferents, responded with a significant delay to nociceptive activation. Besides confirming some previous data obtained in nonhuman primates, the present results open new vistas to the functional organization of the thalamic noxious responses in human beings.

Parallel Thalamic Processing of Nociceptive Information

The 3 nuclei known to receive a major direct STT input in primates (CL, VPL, PuA) responded with indistinguishable onset latencies irrespective of whether they pertained to the lateral (VPL), medial (CL), or posterior thalamic groups (PuA), indicating that thalamic nuclei in different regions are activated simultaneously by peripheral nociceptive stimuli. It is commonly accepted that the roles in perception played by the medial and lateral thalamus differ markedly. The lack of somatotopic organization of terminal axons within primates' medial nuclei, in particular the CL and mediodorsal (Mehler et al. 1960; Lu and Willis 1999), lent substance to the conclusion that the medial STT projections subserve a slow conducted pain information poorly organized for localization (Mehler et al. 1960; Apkarian and Hodge 1989; Willis and Westlund 1997; Craig 2004). In contrast to this conclusion, our data suggest that at least part of the nociceptive processing driven by A-delta fibers and dependent on medial thalamic relays is strictly simultaneous and parallel to that of their lateral counterparts. Giesler et al. (1981) were first to demonstrate that up to one-third of STT neurons in monkeys had bifurcated axons projecting to lateral and medial targets, and could be retrogradely activated by stimulation of both lateral and medial thalamic nuclei (Lu and Willis 1999), thus providing in nonhuman primates anatomical support to the present results in humans. In the same vein, we recently demonstrated that a key-cortical target of medial thalamic nuclei, namely the midanterior cingulate cortex, responded to noxious stimuli in strict concomitance with cortical regions targeted by the lateral thalamus (Frot et al. 2008, 2013). These and our present results strongly uphold the notion of parallel processing with similar timing in lateral and medial STT projections. While lateral thalamo-cortical projections provide sensori-discriminative information to sensory cortices, the medial thalamic input to cingulate structures may subserve rapid orienting reactions to, and withdrawal from, the noxious stimulus, which are known to occur well before the “slow” component of pain experience is fully developed (Dowman 2001; Legrain et al. 2009; Dum et al. 2009).

VPL and PuA Nuclei: Members of a Single Matrix?

While the morphology of central and lateral thalamic responses was clearly dissimilar, there was a striking morphological resemblance between activities evoked in VPL and PuA nuclei (Fig. 1). These 2 nuclei, although anatomically contiguous, have different connectivity and are classified within different nuclear groups (lateral and posterior, respectively) in recent thalamic atlases (Morel et al. 1997; Krauth et al. 2010). Since local field potentials reflect a sum of postsynaptic responses, and are insensitive to action potential spiking (Mitzdorf 1985; Noreña et al. 2010), we can reasonably exclude that the similarity between VPL and PuA response profiles be due to activity in “fibers of passage” transiting through both nuclei. Instead, this similarity is likely to reflect some “anatomical continuity” of the responding cell groups across both nuclei. Based on cytochrome oxidase (CO) staining and calcium-binding protein immunoreactivity, chemically distinct somatosensory compartments have been described in the thalamus, which define whether thalamic cells receive input from lemniscal or STT afferents (Rausell and Jones 1991a, 1991b; Blomqvist et al. 2000; Graziano and Jones 2004). Thus, CO-rich relay cells, immunoreactive for parvalbumin and forming “rods” in the VPL were shown to receive projections from the lemniscal system, whereas STT axons innervated small relay cells immunoreactive for calbindin and surrounding such rods (Rausell and Jones 1991a). Ascending STT fibers have widespread thalamic terminations, in such a way that cells receiving STT input constitute a wide system of calbindin-positive neurons extending over several adjacent nuclei, from the posterior cap of VPL to the PuA, the ventral posterior inferior (VPI) and posterior group (Rausell and Jones 1991a, 1991b; Graziano and Jones 2004). Such “matrix” of STT-receiving cells was considered to represent a wide system “unconstrained by traditional nuclear boundaries” (Rausell et al. 1992), and our results in humans are consistent with this view: a functional domain of STT processing appears to span across several nuclei, and VPL and PuA seem to be part of this continuum. One difference between responses in these 2 regions was however their magnitude, which was clearly superior for electrodes within the PuA.

On the Relative Importance of VPL and PuA as Relay Nuclei for STT Input

Despite a similar shape of VPL and PuA responses, their amplitude markedly differed (Figs 1 and 2) The VPL (and its projections to S1) are still tenaciously considered as prime targets of nociceptive inputs, despite multiple counter-examples in literature dating back at least to William Mehler, who as early as in 1966 stated that [in man], “the principal somatosensory (VPL/VPM) nuclei subserve only an adjunctive function in (…) the central epicritic pain pathway” (Mehler 1966, p.1). In accordance, macrostimulation within the VPL (or Vc) region evoked pain in <10% of patients (Tasker et al. 1982), and cells responding to pin-prick (which is the sensation most resembling that of laser pulses) were “very rarely encountered anywhere in the ventral nuclear group” (Lenz et al. 1987, 1988). Similarly, microstimulation of the VPL (Vc) in patients without somatosensory disorders very rarely evoked pain (2–12% of sites) while the same stimulation consistently induced nonpainful paresthesiae in more than 70–98% of sites (Lenz, Seike, Richardson et al. 1993; Davis et al. 1996; Rezai et al. 1999). In parallel to these observations, Lenz's group showed that the sites where neurons responded to painful heat, and where microstimulation evoked thermo-nociceptive sensations or reproduced a previously experienced pain, were not within the core of the Vc (VPL) nucleus, but rather “at and adjacent to its posterior inferior border”, and toward its medial aspect (Lenz, Seike, Lin et al. 1993; Lenz, Seike, Richardson et al. 1993; Lenz et al. 1995). These sites are consistent with the location of PuA in the present study, whose average coordinates were more posterior, inferior, and medial than those of VPL (see Methods) and also yielded larger field responses than those from the VPL (Figs 1 and 2). The label “PuA” corresponds to the nucleus “ventrocaudalis portae” (Vcpor) in Lenz et al.'s studies, where microstimulation evoked pain sensations more likely than in the VPL proper (Lenz, Seike, Richardson et al. 1993, p. 206). Inasmuch as the magnitude of local field potentials is interpreted as reflecting the importance of synaptic input to the recorded zone, our results suggest that density of STT afferents may be higher in PuA than in VPL. “However, it is also possible that the small response in the VPL be related to its sparse and somatotopically discrete STT innervation (Dum et al. 2009; Lenz et al. 2010; Hong et al. 2011), as well as its wider volume of distribution of afferent axons compared to the PuA, where STT input has to congregate in a relatively small volume. A possible nonsomatotopic location of our VPL contacts relative to the stimulated body area, together with differences in volume distribution may have therefore enhanced the amplitude difference recorded in both structures. In line with a predominant role of PuA in human STT processing, data from patients with focal thalamic lesions recently showed that STT deficits following thalamic stroke were associated with lesions involving the PuA rather than the VPL (Vartiainen et al. 2014), and the PuA (or Vcpor) was recently identified as the thalamic region where thalamic stroke is most likely to produce central pain in humans (Sprenger et al. 2012), even in cases where the VPL and the VMpo region are totally spared (Krause et al. 2012).

Together with the morphological similarity between VPL and PuA responses, these data concur with the notion of a wide functional domain of STT processing in the posterior thalamus, in continuity across several “classical” nuclei (Rausell et al. 1992), but with inhomogeneous cell density in each of them. Both VPL and PuA seem to be part of this continuum, and it is highly likely that more posterior–inferior nuclear groups not recorded in this study, including the VPI nucleus, and the postero-medial zone sometimes labeled “VMpo” (Craig et al. 1994), may also pertain to this continuous functional domain (Graziano and Jones 2004).

Thalamo-Cortical Connectivity Patterns of the Different Nuclei Explored

Patterns of functional connectivity with cortical areas, as assessed with spectral phase coherence, greatly differed in medial and lateral nuclei. Functional thalamo-cortical connectivity of VPL and PuA was spatially limited (Fig. 3), in agreement with anatomical studies showing that the main projections of the postero-lateral nuclei are mostly directed toward somatosensory regions (review in Lenz et al. 2010), including the posterior insula and posterior parietal areas (Burton and Jones 1976; Jones et al. 1979; Mufson and Mesulam 1984; Yeterian and Pandya 1985; Friedman and Murray 1986). In view of the connectivity patterns of PuA in nonhuman primates, one may be surprised by its lack of significant coherence with parietal area 7 in our patients. One likely reason may be the limited recording sampling of this cortical area by our orthogonal electrodes, which only explored a very restricted part of the parietal lobe.

In contrast with the limited connectivity pattern of lateral–posterior nuclei, functional connections of CL appeared much more extended, in accordance with its wide-ranging cortical projections. The CL is connected to an extensive array of cortical and striatal areas involved in somato-motor control and attentional orienting (Royce 1983; Schiff and Purpura 2002; Van Der Werf et al. 2002). It has reciprocal monosynaptic connections with the medial frontal regions supporting arousal regulation, and stimulation of the CL was able to improve arousal indexes in patients with minimal conscious state (a near-vegetative state following coma), in concomitance with activation of midfrontal, cingulate, and motor cortical regions (Schiff et al. 2007). All these data support the importance of CL cortical projections in the motor, cognitive, and alerting aspects of pain processing (Albe-Fessard et al. 1985).

The PuM was also characterized by a widespread cortical connectivity, which even surpassed that of the CL for high-frequency γ activities (Fig. 4). It is noticeable that such an extensive connectivity was observed in a nucleus devoid of direct STT afferents, and showing the longest response latencies to STT activation. This triad of anatomo-functional features (lack of STT afferents, longest response latency, and widest cortical connectivity) is consistent with the associative attributes and anatomical interconnections of PuM with regions in parietal, frontal, and temporal lobes, including higher order cortices and paralimbic association's areas (reviews in Cappe et al. 1997; Robinson and Cowie 1997; Shipp 2003). Due to its pattern of widespread and spatially overlapping cortical inputs, the PuM is considered as an important node in the trans-thalamic routing of cortico-cortical input (Baleydier and Mauguiere 1985; Morel et al. 1997; Shipp 2003; Cappe et al. 2009). Indeed, cortico-thalamic feed-forward projections combined with a subsequent thalamo-cortical transmission is viewed as a fast and secure mode ensuring the transfer of information between remote cortical districts through a “cortico-thalamo-cortical” route (Guillery 1995; Rouiller and Welker 2000; Sherman 2007; Cappe et al. 2009). All this suggests a role of the PuM nucleus in synchronizing activities of distant cortical areas, hence sustaining the formation of synchronized trans-areal assemblies and contributing to the ultimate access of noxious input to conscious awareness.

Limitations of the Study

In the present work, we analyzed thalamic responses with nociceptive somatosensory stimuli only, without any control with responses to non-nociceptive stimuli. Response latency values, however, in the order of 150–400 ms, are exclusively compatible with the timing of activation of the STT and not of the medial lemniscus, the activation of which gives rise to responses in the 15–50 ms range (Fukushima et al. 1976; Thoden et al. 1979; Rektor et al. 2001), hence any contamination with non-nociceptive signals appears negligible. Although infrared laser pulses activate concomitantly A-delta and C receptors (Bromm and Treede 1984; Marchandise et al. 2014), the evoked responses that we recorded remained limited to the A-delta range. This phenomenon is known as the “first come first served” effect (Garcia-Larrea 2004), and limits our interpretation to A-delta-driven thalamic signals. Later volleys conveying C-fiber input do not elicit LEPs, but may appear as changes in oscillatory activity (Mouraux et al. 2003) which can pass on to cortical areas and be reflected by spectral coherence changes. In this respect, the significant increase of phase coherence between the CL nucleus and the cortex during the late (400–700 ms) analysis window may reflect the sequential activation of medial thalamus by 2 distinct (A-delta and C) STT volleys.

Significant phase coherence between signals recorded from 2 structures does not by itself prove that one structure exerts a causal influence over the other. Functional relationship may be the result of functional connections through other intermediary structures, which were not recorded here (Liu et al. 2011). Moreover, since coherence values at baseline were not included in the analyses, part of the results might reflect thalamo-cortical activity independent from nociceptive processing, or related to preprocessing activities such as anticipation or attentional orienting. Finally, despite having recorded simultaneously from several thalamic nuclei, we could not gather data from other posterior–inferior thalamic regions, including the so-called VMpo (Craig et al. 1994; Blomqvist et al. 2000), which may be also crucial nods of STT processing. The data presented here are therefore incomplete, and should be hopefully augmented by further recordings in the forthcoming years.

Funding

Supported by the French Society for Pain Evaluation and Therapy (Translational Research Grant 2012-14), the LABEX CORTEX (ANR-11-LABX-0042; ANR-11-IDEX-0007), and a INSERM Interface Grant to H.B.

Notes

Conflict of Interest: None declared.

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Author notes

In this work, we followed the nomenclature of thalamic nuclei from Hirai and Jones (1989); Morel et al. (1997), and Krauth et al. (2010). The nuclei labeled here as “ventro-postero-lateral” (VPL) and “anterior pulvinar” (PuA) correspond to those labeled “ventrocaudal” (Vc) and “ventrocaudalis portae” (Vcpo), respectively, in some of the papers we cite, which followed Hassler's (1959) nomenclature.