C.C. Liu

Painful stimuli evoke potentials recorded from the medial temporal lobe in humans.

The role of human medial temporal structures in fear conditioning has led to the suggestion that neurons in these structures might respond to painful stimuli. We have now tested the hypothesis that recordings from these structures will demonstrate potentials related to the selective activation of cutaneous nociceptors by a painful laser stimulus (laser evoked potential, LEP) (Kenton B, Coger R, Crue B, Pinsky J, Friedman Y, Carmon A (1980) Neurosci Lett 17:301-306). Recordings were carried out through electrodes implanted bilaterally in these structures for the investigation of intractable epilepsy. Reproducible LEPs were commonly recorded both bilaterally and unilaterally, while LEPs were recorded at contacts on the left (9/14, P=0.257) as commonly as on the right (5/14), independent of the hand stimulated. Along electrodes traversing the amygdala the majority of LEPs were recorded from dorsal contacts near the central nucleus of the amygdala and the nucleus basalis. Stimulus evoked changes in theta activity were observed at contacts on the right at which isolated early negative LEPs (N2*) responses could be recorded. Contacts at which LEPs could be recorded were as commonly located in medial temporal structures with evidence of seizure activity as on those without. These results demonstrate the presence of pain-related inputs to the medial temporal lobe where they may be involved in associative learning to produce anxiety and disability related to painful stimuli.

Attention to painful cutaneous laser stimuli evokes directed functional connectivity between activity recorded directly from human pain-related cortical structures

&NA; Our previous studies show that attention to painful cutaneous laser stimuli is associated with functional connectivity between human primary somatosensory cortex (SI), parasylvian cortex (PS), and medial frontal cortex (MF), which may constitute a pain network. However, the direction of functional connections within this network is unknown. We now test the hypothesis that activity recorded from the SI has a driver role, and a causal influence, with respect to activity recorded from PS and MF during attention to a laser. Local field potentials (LFP) were recorded from subdural grid electrodes implanted for the treatment of epilepsy. We estimated causal influences by using the Granger causality (GRC), which was computed while subjects performed either an attention task (counting laser stimuli) or a distraction task (reading for comprehension). Before the laser stimuli, directed attention to the painful stimulus (counting) consistently increased the number of GRC pairs both within the SI cortex and from SI upon PS (SI > PS). After the laser stimulus, attention to a painful stimulus increased the number of GRC pairs from SI > PS, and SI > MF, and within the SI area. LFP at some electrode sites (critical sites) exerted GRC influences upon signals at multiple widespread electrodes, both in other cortical areas and within the area where the critical site was located. Critical sites may bind these areas together into a pain network, and disruption of that network by stimulation at critical sites might be used to treat pain. Electrical activity recorded from the somatosensory cortex drives activity recorded elsewhere in the pain network and may bind the network together; disruption of that network by stimulation at critical sites might be used to treat pain.

Spatial attention to thermal pain stimuli in subjects with visual spatial hemi-neglect: extinction, mislocalization and misidentification of stimulus modality.

&NA; One approach to the study of disordered spatial attention is to carry out tests of extinction, in which stimuli are detected on the left when they are presented on the left alone, but not when both sides are stimulated simultaneously in a dual simultaneous stimulation (DSS) protocol. Extinction has been documented for multiple sensory modalities, but not for thermal pain stimuli, to our knowledge. We now test the hypothesis that subjects with visual spatial neglect (hemi‐neglect) will have alterations in thermal pain sensation which are related to abnormal spatial attention. The results demonstrate that thermal pain extinction of hot and cold pain stimuli occurs in a proportion of subjects with hemi‐neglect. In the subjects with visual spatial hemi‐neglect but without thermal pain extinction, the sensation of the thermal pain stimulus on the affected (left) side was not extinguished but was often localized to the unaffected (right) side, and the submodality of the stimulus (cold or hot) was often misidentified. Ratios indicating the magnitude of extinction, mislocalization and misidentification were significantly larger on the left side of subjects with visual spatial neglect than in healthy controls or in controls with stroke but without hemineglect. The proportion of subjects with thermal pain extinction, mislocalization, or misidentification was significantly higher in subjects with hemi‐neglect than those in either control group. These results demonstrate that disordered attention exerts a powerful effect upon the perception of both the location and the quality of thermal pain stimuli.

Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus

The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala.

A Painful Cutaneous Laser Stimulus Evokes Responses From Single Neurons in the Human Thalamic Principal Somatic Sensory Nucleus Ventral Caudal (Vc)

Cutaneous application of painful radiant heat laser pulses evokes potentials (laser-evoked potentials) that can be recorded from scalp or intracranial electrodes. We have now tested the hypothesis that the response of thalamic neurons to a cutaneous laser stimulus occurs at latencies predicted by the conduction delay between the periphery and the thalamus. We have carried out recordings from human thalamic neurons in the principal sensory nucleus (ventral caudal) in patients undergoing awake surgery for the treatment of tremor. The results demonstrate that many neurons respond to the laser with early and/or late latency peaks of activity, consistent with conduction of the response to the laser stimulus through pathways from Adelta and C fibers to the thalamus. These peaks were of short duration, perhaps due to the somatotopic- and modality-specific arrangements of afferent pathways to the thalamus. The responses of these thalamic neurons to the laser stimulus sometimes included low-threshold spike (LTS) bursts of action potentials, consistent with previous studies of different painful stimuli. A prior study has demonstrated that spike trains characterized by common LTS bursts such as the intermediate (I) category spontaneously change their category more commonly than do those without LTS bursts (NG: nongrouped category) during changes in the cognitive task. Spike trains of laser-responsive neurons were more common in the I category, whereas those of laser nonresponsive neurons were more common in the NG category. Therefore neuronal spike trains in the I category may mediate shifts in endogenous or cognitive pain-related behavior.

Studies of properties of "Pain Networks" as predictors of targets of stimulation for treatment of pain

Two decades of functional imaging studies have demonstrated pain-related activations of primary somatic sensory cortex (S1), parasylvian cortical structures (PS), and medial frontal cortical structures (MF), which are often described as modules in a “pain network.” The directionality and temporal dynamics of interactions between and within the cortical and thalamic modules are uncertain. We now describe our studies of these interactions based upon recordings of local field potentials (LFPs) carried out in an epilepsy monitoring unit over the one week period between the implantation and removal of cortical electrodes during the surgical treatment of epilepsy. These recordings have unprecedented clarity and resolution for the study of LFPs related to the experimental pain induced by cutaneous application of a Thulium YAG laser. We also used attention and distraction as behavioral probes to study the psychophysics and neuroscience of the cortical “pain network.” In these studies, electrical activation of cortex was measured by event-related desynchronization (ERD), over SI, PS, and MF modules, and was more widespread and intense while attending to painful stimuli than while being distracted from them. This difference was particularly prominent over PS. In addition, greater perceived intensity of painful stimuli was associated with more widespread and intense ERD. Connectivity of these modules was then examined for dynamic causal interactions within and between modules by using the Granger causality (GRC). Prior to the laser stimuli, a task involving attention to the painful stimulus consistently increased the number of event-related causality (ERC) pairs both within the SI cortex, and from SI upon PS (SI > PS). After the laser stimulus, attention to a painful stimulus increased the number of ERC pairs from SI > PS, and SI > MF, and within the SI module. LFP at some electrode sites (critical sites) exerted ERC influences upon signals at multiple widespread electrodes, both in other cortical modules and within the module where the critical site was located. In summary, critical sites and SI modules may bind the cortical modules together into a “pain network,” and disruption of that network by stimulation might be used to treat pain. These results in humans may be uniquely useful to design and optimize anatomically based pain therapies, such as stimulation of the S1 or critical sites through transcutaneous magnetic fields or implanted electrodes.

Painful cutaneous laser stimuli induce event-related oscillatory EEG activities that are different from those induced by nonpainful electrical stimuli

The non-phase-locked EEG response to painful stimuli has usually been characterized as decreased oscillatory activity (event-related desynchronization, ERD) in the alpha band. Increased activity (event-related synchronization, ERS) in the gamma band has been reported more recently. We have now tested the hypothesis that the non-phase-locked responses to nonpainful electric cutaneous stimuli are different from those to painful cutaneous laser stimuli when the baseline salience of the two stimuli is the same and the salience during the protocol is modulated by count laser and count electric tasks. Both of these stimuli were presented in random order in a single train at intensities that produced the same baseline salience in the same somatic location. The response to the laser stimulus was characterized by five windows (designated windows I-V) in the time-frequency domain: early (200-400 ms) and late (600-1,400 ms) delta/theta ERS, 500-900 ms alpha ERD, 1,200-1,600 ms beta ERS (rebound), and 800-1,200 ms gamma ERS. Similar ERS/ERD windows of activity were found for the electric stimulus. Individual participants very commonly had activity in windows consistent with the overall analysis. Linear regression of ERS/ERD for parietal channels was most commonly found for sensory (pain or unpleasantness)- or attention (salience)-related measures. Overall, the main effect for modality was found in window I-delta/theta and window V-gamma, and the Modality with Task interaction was found in all five windows. All significant interaction terms included Modality as a factor. Therefore, Modality was the most common factor explaining our results, which is consistent with our hypothesis.

Cross-frequency coupling in deep brain structures upon processing the painful sensory inputs

Cross-frequency coupling has been shown to be functionally significant in cortical information processing, potentially serving as a mechanism for integrating functionally relevant regions in the brain. In this study, we evaluate the hypothesis that pain-related gamma oscillatory responses are coupled with low-frequency oscillations in the frontal lobe, amygdala and hippocampus, areas known to have roles in pain processing. We delivered painful laser pulses to random locations on the dorsal hand of five patients with uncontrolled epilepsy requiring depth electrode implantation for seizure monitoring. Two blocks of 40 laser stimulations were delivered to each subject and the pain-intensity was controlled at five in a 0-10 scale by adjusting the energy level of the laser pulses. Local-field-potentials (LFPs) were recorded through bilaterally implanted depth electrode contacts to study the oscillatory responses upon processing the painful laser stimulations. Our results show that painful laser stimulations enhanced low-gamma (LH, 40-70 Hz) and high-gamma (HG, 70-110 Hz) oscillatory responses in the amygdala and hippocampal regions on the right hemisphere and these gamma responses were significantly coupled with the phases of theta (4-7 Hz) and alpha (8-1 2 Hz) rhythms during pain processing. Given the roles of these deep brain structures in emotion, these findings suggest that the oscillatory responses in these regions may play a role in integrating the affective component of pain, which may contribute to our understanding of the mechanisms underlying the affective information processing in humans.

Functional role of induced gamma oscillatory responses in processing noxious and innocuous sensory events in humans

Gamma time-frequency responses (TFRs) induced by painful laser in the contralateral primary somatosensory (SI) cortex have been shown to correlate with perceived pain-intensity in human. Given the functional roles of gamma TFRs in the cortical spaces, it remains unclear whether such a relationship is sustained for other brain regions where the laser-evoked potentials (LEPs) are presented. In this study, we delivered the painful laser pluses at random pain-intensity levels (i.e. strong, medium and weak) in a single train to the dorsal hand of six patients with uncontrolled epilepsy. The laser stimulus produced a painful pinprick sensation by activating nociceptors located in the superficial layers of the skin. For each patient, arrays of >64 subdural electrodes were implanted directly covering the contralateral SI, parasylvian (PS) and medial frontal (MF) cortices to study the stimulus related gamma (TFRs) in the neocortex. In addition, using the same stimulation paradigm, the modality specificity of gamma TFRs was further examined by applying innocuous vibrotactile stimuli to the same regions of the dorsal hand in a separated group of five patients. Our results showed that gamma TFRs are not modality specific, but the largest gamma TFRs were consistently found within the SI region and noxious laser elicited significantly stronger gamma TFRs than innocuous nonpainful vibratory stimuli. Furthermore, stronger pain induced stronger gamma TFRs in the cortices of SI (r=0.4, p<0.001) and PS (r=0.29, p=0.005). Given that potentially harmful noxious stimulus would automatically capture greater attention than the innocuous ones, our results support the hypothesis that the degree of SI and PS gamma TFRs is associated with an attentional drive provoked by painful stimuli.

EEG analysis reveals widespread directed functional interactions related to a painful cutaneous laser stimulus

During attention to a painful cutaneous laser stimulus, event-related causality (ERC) has been detected in recordings from subdural electrodes implanted directly over cortical modules for the treatment of epilepsy. However, these studies afforded limited sampling of modules and did not examine interactions with a nonpainful stimulus as a control. We now sample scalp EEG to test the hypothesis that attention to the laser stimulus is associated with poststimulus ERC interactions that are different from those with attention to a nonpainful stimulus. Subjects attended to (counted) either a painful laser stimulus (laser attention task) or a nonpainful electrical cutaneous stimulus that produced distraction from the laser (laser distraction task). Both of these stimuli were presented in random order in a single train. The intensities of both stimuli were adjusted to produce similar baseline salience and sensations in the same cutaneous territory. The results demonstrated that EEG channels with poststimulus ERC interactions were consistently different during the laser stimulus versus the electric stimulus. Poststimulus ERC interactions for the laser attention task were different from the laser distraction task. Furthermore, scalp EEG frontal channels play a driver role while parietal temporal channels play a receiver role during both tasks, although this does not prove that these channels are connected. Sites at which large numbers of ERC interactions were found for both laser attention and distraction tasks (critical sites) were located at Cz, Pz, and C3. Stimulation leading to disruption of sites of these pain-related interactions may produce analgesia for acute pain.