Painful cutaneous laser stimuli induce event-related gamma-band activity in the lateral thalamus of humans.

Although the thalamus is an important module in "pain networks," there are few studies of the effect of experimental pain upon thalamic oscillations. We have now examined the hypothesis that, during a series of painful cutaneous laser stimuli, thalamic signals will show stimulus-related gamma-band spectral activity, which is modulated by attention to vs. distraction from the painful stimulus. When the series of laser stimuli was presented, attention was focused by counting the laser stimuli (count laser task), while distraction was produced by counting backward (count back plus laser task). We have studied the effect of a cutaneous laser on thalamic local field potentials and EEG activity during awake procedures (deep brain stimulation implants) for the treatment of essential tremor. At different delays after the stimulus, three low gamma- (30-50 Hz) and two high gamma-band (70-90 Hz) activations were observed during the two tasks. Greater high-gamma activation was found during the count laser task for the earlier window, while greater high-gamma activation was found during the count back plus laser task for the later window. Thalamic signals were coherent with EEG signals in the beta band, which indicated significant synchrony. Thalamic cross-frequency coupling analysis indicated that the phase of the lower frequency activity (theta to beta) modulated the amplitude of the higher frequency activity (low and high gamma) more strongly during the count laser task than during the count back plus laser task. This modulation might result in multiplexed signals each encoding a different aspect of pain.

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.

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.

Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain.

Thalamic structures involved in the unpleasant emotional or affective aspect of pain are poorly understood. We now describe studies of the region of the thalamic principal somatosensory nucleus (Vc) performed before thalamotomy for tremor in a patient who also had panic disorder. Microstimulation in the region posterior to Vc evoked chest pain, including a strong affective dimension, almost identical to that occurring during his panic attacks, as measured using a questionnaire. Results in our other patients indicate that stimulation-associated pain with a strong affective dimension occurred only in those patients who had previously experienced spontaneous pain with a strong affective component. These results are consistent with stimulation-evoked activation of limbic structures, which are connected through cortex with the region posterior to Vc and involved in the affective dimension of pain through conditioning by previous experience.

Neural activities of tactile cross-modal working memory in humans: an event-related potential study.

In the present study, we examined the neural mechanisms underlying cross-modal working memory by analyzing scalp-recorded event-related potentials (ERPs) from normal human subjects performing tactile-tactile unimodal or tactile-auditory cross-modal delay tasks that consisted of stimulus-1 (S-1, tactile), interval (delay), and stimulus-2 (S-2, tactile or auditory). We hypothesized that there would be sequentially discrete task-correlated changes in ERPs representing neural processes of tactile working memory, and in addition, significant differences would be observed in ERPs between the unimodal task and the cross-modal task. In comparison to the ERP components in the unimodal task, two late positive ERP components (LPC-1 and LPC-2) evoked by the tactile S-1 in the delay of the cross-modal task were enhanced by expectation of the associated auditory S-2 presented at the end of the delay. Such enhancement might represent neural activities involved in cross-modal association between the tactile stimulus and the auditory stimulus. Later in the delay, a late negative component (LNC) was observed. The amplitude of LNC depended on information retained during the delay, and when the same information was retained, this amplitude was not influenced by modality or location of S-2 (auditory S-2 through headphones, or tactile S-2 on the left index finger). LNC might represent the neural activity involved in working memory. The above results suggest that the sequential ERP changes in the present study represent temporally distinguishable neural processes, such as the cross-modal association and cross-modal working memory.

Irregularity distinguishes limb tremor in cervical dystonia from essential tremor.

INTRODUCTION: Patients with cervical dystonia (CD) often have limb tremor that is clinically indistinguishable from essential tremor (ET). Whether a common central mechanism underlies the tremor in these conditions is unknown. We addressed this issue by quantifying limb tremor in 19 patients with CD and 35 patients with ET. METHOD: Postural, resting and kinetic tremors were quantified (amplitude, mean frequency and regularity) using a three-axis accelerometer. RESULTS: The amplitude of limb tremor in ET was significantly higher than in CD, but the mean frequency was not significantly different between the groups. The cycle-to-cycle variability of the frequency (ie the tremor irregularity), however, was significantly greater (approximately 50%) in CD. Analysis of covariance excluded the possibility that the increased irregularity was related to the smaller amplitude of tremor in CD (ANCOVA: p = 0.007, F = 5.31). DISCUSSION: We propose that tremor in CD arises from oscillators with different dynamic characteristics, producing a more irregular output, whereas the tremor in ET arises from oscillators with similar dynamic characteristics, producing a more regular output. We suggest that variability of tremor is an important parameter for distinguishing tremor mechanisms. It is possible that changes in membrane kinetics based on the pattern of ion channel expression underlie the differences in tremor in some diseases.

Analysis of synchrony demonstrates that the presence of "pain networks" prior to a noxious stimulus can enable the perception of pain in response to that stimulus.

Our previous study has shown that directed attention to a painful stimulus is associated with increased synchrony between electrocorticographic (ECoG) oscillations in pain-related cortical structures. We now test the hypothesis that the synchrony or functional connectivity of this pain network differs between events during which pain is or is not perceived (pain or non-pain events) in response to a noxious cutaneous laser stimulus. ECoG recordings were made through subdural electrodes implanted in a patient for the treatment of epilepsy. The patient was instructed that the stimulus could be painful or non-painful on any given presentation. Synchrony between ECoG signals at different sites was measured during the pre-stimulus interval, and the difference in the number of sites with significant pre-stimulus synchrony was compared between pain and non-pain events. Pre-stimulus synchrony was more common during pain versus non-pain events among electrodes overall, and in the subset of electrodes at which laser-evoked potentials (LEPs) were recorded. This difference between pain and non-pain events was also significant for the subset of electrodes over medial cortex, including anterior cingulate cortex (ACC), but not for subsets of electrodes over the superior and inferior convexity, including primary somatosensory (S1) and parasylvian cortex (PS), respectively. These results suggest that dynamic changes in the functional connectivity between ACC and other cortical regions enable the perception of pain in response to noxious stimuli.

Sensory, Motor and Intrinsic Mechanisms of Thalamic Activity related to Organic and Psychogenic Dystonia.

The thalamus is a critical module in the circuit which has been associated with movement disorders including dystonia. This circuit extends from cortex to striatum to pallidum to the thalamic nucleus Ventral Lateral anterior (VLa) to cortex and can be studied by activity recorded during thalamic stereotactic surgery for the treatment of dystonia. Neuronal recordings in the VLa nucleus show low frequency modulation of firing that is correlated with and leads the low frequency modulation of EMG activity; this EMG activity is characteristic of dystonia. Immediately posterior is the Ventral Lateral posterior (VLp) nucleus which, in controls (patients with tremor or chronic pain), is characterized by deep sensory cells which fire at short latency in response to movement of a single joint or to stimulation of deep structures, such as muscles, tendons and joints. In patients with dystonia, neurons with this sensory activity are much more common than in controls and single neurons often respond to movement of multiple joints. In controls operated for the treatment of tremor or chronic pain many neurons in both nuclei are activated during active or involuntary joint movements, such as tremor or dystonia. The active joint movement related to the firing of a cell is usually in the opposite direction to the passive joint movement which causes that cell to fire. This linkage of active or involuntary and passive joint movement is unfocussed in dystonia. The involuntary dystonic joint movement best correlated with firing of a neuron may not activate the neuron when it occurs as a passive movement, while multiple other passive movements will activate the neuron. These linkages may explain the overflow of isolated voluntary activity to multiple other muscles that is seen in dystonia. The activity of either nucleus may have a critical role in dystonia since their disruption by stimulation or lesioning can decrease dystonia.

Vigilance behaviors and EEG activity in sustained attention may affect acute pain.

During Sustained Attention to stimuli across many modalities neural activity often decreases over time on task, while Errors in task performance increase (Vigilance Decrement). Sustained Attention to pain has rarely been investigated experimentally despite its clinical significance. We have employed a Sustained Attention protocol (Continuous Performance Task, CPT) in which the subject counts painful laser stimuli (targets) when they occur randomly in a prolonged train of nonpainful nontargets. We hypothesize that the magnitude of the poststimulus oscillatory power divided by baseline power (Event-Related Spectral Perturbation, ERSP - scalp EEG) over Frontoparietal structures will decrease at all frequencies with time on task, while Beta ERSP (14-30Hz) will be correlated with Error Rates in performance of the CPT. During the CPT with a painful target ERSP was found in four separate Windows, as defined by both their frequency band and the time after the stimulus. A Vigilance Decrement was found which confirms that Sustained Attention to pain was produced by this CPT. In addition, Error Rates was correlated inversely with laser energy, and with ratings of pain unpleasantness and salience. Error Rates also were related directly to the Beta ERSP Window at scalp EEG electrodes over the central sulcus. Over time on task, the ERSP magnitude decreased in Alpha (8-14Hz) Window, was unchanged in early and late Delta/Theta Windows (0-8Hz), and increased in the Beta Window. The increase in Beta ERSP and a decrease in the Alpha ERSP occurred at the same EEG electrode over the parietal lobe to a significant degree across subjects. Overall, Beta activity increases with time on task, and with higher Error Rates as in the case of other modalities. In the case of pain increased Errors correspond to misidentification of painful and nonpainful stimuli and so modulate the sensation of pain under the influence of Sustained Attention.

Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than Expectancy.

Imaging studies have described hemodynamic activity during fear conditioning protocols with stimulus trains in which a visual conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US, painful laser pulse) while another visual stimulus is unpaired (CS-). We now test the hypothesis that CS Event Related Spectral Perturbations (ERSPs) are related to ratings of CS Expectancy (likelihood of pairing with the US), Valence (unpleasantness) and Salience (ability to capture attention). ERSP windows in EEG were defined by both time after the CS and frequency, and showed increased oscillatory power (Event Related Synchronization, ERS) in the Delta/Theta Windows (0-8Hz) and the Gamma Window (30-55Hz). Decreased oscillatory power (Event Related Desynchronization - ERD) was found in Alpha (8-14Hz) and Beta Windows (14-30Hz). The Delta/Theta ERS showed a differential effect of CS+ versus CS- at Prefrontal, Frontal and Midline Channels, while Alpha and Beta ERD were greater at Parietal and Occipital Channels early in the stimulus train. The Gamma ERS Window increased from habituation to acquisition over a broad area from frontal and occipital electrodes. The CS Valence and Salience were greater for CS+ than CS-, and were correlated with each other and with the ERD at overlapping channels, particularly in the Alpha Window. Expectancy and CS Skin Conductance Response were greater for CS+ than CS- and were correlated with ERSP at fewer channels than Valence or Salience. These results suggest that Alpha ERSP activity during fear conditioning reflects Valence and Salience of the CSs more than conditioning per se.

Psychophysics of CNS pain-related activity: binary and analog channels and memory encoding.

The forebrain neuronal system signaling pain has been poorly characterized. The pain pathway afferent to the thalamus may be a labeled line consisting of neurons in the pain-signaling pathway to the brain (spinothalamic tract, STT) that respond only to painful stimuli. It has recently been proposed that the STT contains a series of analog-labeled lines, each signaling a different aspect of the internal state of the body (interoception), for example, visceral/cold/itch sensations. In this view, pain is the unpleasant emotion produced by disequilibrium of the internal state. The authors now show that stimulation of an STT receiving zone (thalamic principal somatic sensory nucleus, ventral caudal) in awake humans produces two different exteroceptive responses. The first is a binary response signaling the presence of painful stimuli. The second is an analog response in which nonpainful and painful sensations are graded with intensity of the stimulus. Such stimulation can evoke both the sensory and emotional components of previously experienced pain. These results illustrate the diverse functions of human pain signaling pathways.

Modulation of somatosensory event-related potential components in a tactile-visual cross-modal task.

Human tactile discrimination studies have shown that visual stimuli enhance tactile performance. Other studies on event-related potentials showed that somatosensory N140 was enhanced when attention of human subjects was directed to tactile stimuli. Therefore, we hypothesized that N140 would be modulated when human subjects performed tactile cross-modal delay tasks. Scalp-event-related potentials were recorded from normal subjects performing either a tactile-tactile unimodal, or a tactile-visual cross-modal delayed matching-to-sample task. Identical tactile stimuli were used in both tasks. N140 component evoked by the tactile stimuli was enhanced in the cross-modal task. Enhancement of this component was also observed in control cross-modal tasks. The results suggest that tactile-visual cross-modal association affects tactile sensory-perceptual processes in humans.

Fractal characteristics of human Parkinsonian neuronal spike trains.

Fractal analysis was applied to human pallidal neuronal spike trains recorded from patients with Parkinson's disease during ablative surgery of the internal segment of the globus pallidus. Fractal dynamics was quantified by computing the scaling exponent with the average wavelet coefficient approach. We observed fractal persistent correlation in the fluctuation of the interspike intervals of neuronal spike trains recorded in the internal segment of the globus pallidus both before and after the administration of dopamine agonist apomorphine. However, there was a significant increase in the scaling exponent during the "on" state after apomorphine administration as compared with the parkinsonian "off" state prior to apomorphine. In addition, we observed a statistically significant decrease in the average firing rate in the transition from the "off" to the "on" state. We conclude that robust fractal dynamics can be observed in single neurons in the human CNS, indicating that human neuronal dynamics of the internal segment of the globus pallidus are essentially a nonlinear and nonequilibrium process, with a long-range correlation or memory extending across many time scales. Accompanying the "on" state after apomorphine administration was an improvement in the long-range persistent correlation as compared with the more random dynamics in the "off" state. A scaling exponent signaling a breakdown or modification in long-range correlation in a single neuron may serve as a useful indicator of a dysfunctional network in the human CNS.

Plasticity of pain-related neuronal activity in the human thalamus.

Strokes and other forms of injury to the central nervous system cause changes in function because of the injuries themselves and indirectly because injuries cause expression of neural plasticity. Studies in humans undergoing neurosurgical procedures for implantation of electrodes for deep brain stimulation and for making lesions in the brain have contributed understanding of both normal and abnormal functions of the somatic sensory system. This chapter will specifically discuss the reorganization of the ventral caudal (Vc) sensory nucleus of the thalamus that occurs in connection with pain conditions after strokes and spinal cord injuries. It is shown that pain is associated with expression of neural plasticity that alters maps of noxious and innocuous stimulation in the thalamus and affect processing of sensory information. Results from studies of neural activity in the thalamus in humans will be compared with results from animal studies.

Endogenous and exogenous modulators of potentials evoked by a painful cutaneous laser (LEPs).

Little is known about the specific functions of the human cortical structures receiving nociceptive input, their relationship to various dimensions of pain, and the modulation of these inputs by attention. We now review studies demonstrating the subdural potentials evoked by a cutaneous laser stimulus which produces a pure pain sensation by selective activation of cutaneous nociceptors (LEPs). These LEPs were localized over human anterior and middle cingulate (A & MCC), somatosensory (S1) and parasylvian (PS) cortices. LEP, lesion and imaging data define pain-related elements within each of these structures: insula and parietal operculum within PS, anterior and middle cingulate cortex, and possibly Brodman's areas 3a, 3b and 1 within SI. LEPs recorded over each of these areas is modulated with laser intensity and evoked pain. Attention to the painful laser produces an increase in the amplitude of LEPs over all three cortical areas and emergence of a late positive potential over ACC alone. These studies provide clear evidence of human cortical structures receiving nociceptive input and the modulation of that input by exogenous (e.g. laser intensity) and endogenous factors (e.g. directed attention).

EMG activity and neuronal activity in the internal globus pallidus (GPi) and their interaction are different between hemiballismus and apomorphine induced dyskinesias of Parkinson's disease (AID).

The nature of electromyogram (EMG) activity and its relationship to neuronal activity in the internal globus pallidus (GPi) have not previously been studied in hyperkinetic movement disorders. We now test the hypothesis that GPi spike trains are cross-correlated with EMG activity during apomorphine-induced dyskinesias of Parkinson's disease (AID), and Hemiballism. We have recorded these two signals during awake stereotactic pallidal surgeries and analyzed them by cross-correlation of the raw signals and of peaks of activity occurring in those signals. EMG signals in Hemiballism usually consist of 'sharp' activity characterized by peaks of activity with low levels of activity between peaks, and by co-contraction between antagonistic muscles. Less commonly, EMG in Hemiballism shows 'non-sharp' EMG activity with substantial EMG activity between peaks; 'non-sharp' EMG activity is more common in AID. Therefore, these hyperkinetic disorders show substantial differences in peripheral (EMG) activity, although both kinds of activity can occur in both disorders. Since GPi spike×EMG spectral and time domain functions demonstrated inconsistent cross-correlation in both disorders, we studied peaks of activity in GPi neuronal and in EMG signals. The peaks of GPi activity commonly show prolonged cross-correlation with peaks of EMG activity, which suggests that GPi peaks are related to the occurrence of EMG peaks, perhaps by transmission of GPi activity to the periphery. In Hemiballism, the presence of direct GPi peak×EMG peak cross-correlations at the site where lesions relieve these disorders is evidence that gradual changes in peak GPi neuronal activity are directly involved in Hemiballism.

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.

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.

Nitric oxide modulates endothelin 1-induced Ca2+ mobilization and cytoskeletal F-actin filaments in human cerebromicrovascular endothelial cells.

A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-1-stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-1 interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1-mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO-ET-1 interactions may contribute to regulation of microvascular function.

Responses of neurons in the region of human thalamic principal somatic sensory nucleus to mechanical and thermal stimuli graded into the painful range.

The role of the region of the principal somatic sensory nucleus of the human thalamus (ventral caudal - Vc) in signaling painful sensations is unclear. We have now studied the response of cells (n = 57) in this region to both thermal and mechanical stimuli graded into the painful range during surgeries (n = 24) for treatment of movement disorders. Fifteen cells had a graded response to mechanical stimuli extending into the painful range and, thus, were classified in the wide dynamic range (WDR) category. The mean stimulus-response function of cells in the WDR class, normalized to baseline, showed a fourfold mean increase in firing rate above baseline across the mechanical series of stimuli. Seven of these cells responded to heat stimuli (WDR-H) and two responded to cold stimuli (WDR-C). Twenty-five cells were in a class (multiple receptive - MR) that showed a response to both brush and compressive stimuli, although the responses were not graded into the painful range. Three of these cells (MR-H) had a response to heat stimuli and five cells responded to cold stimuli (MR-C). Nine cells responded to brushing without a response to the compressive stimuli (low threshold - LT). Cells responsive to painful mechanical and thermal stimuli were located throughout the thalamic region where cells responded to nonpainful cutaneous stimulation. These results show that cells in the region of the human thalamic principal somatic sensory nucleus respond to mechanical and thermal stimuli extending into the painful range.