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.

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.

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.

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.

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.

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.

Thalamic post-inhibitory bursting occurs in patients with organic dystonia more often than controls.

We now test the hypothesis that post-inhibitory bursting in the human pallidal receiving nucleus of the thalamus (ventral oral) mediates inhibitory pallido-thalamic transmission during dystonia. We have compared thalamic single neuron activity in nine patients with organic dystonia to that in a patient with psychogenic dystonia (Psyd) and in healthy waking monkeys. In organic dystonia, EMG power is commonly concentrated at the lowest frequency of the smoothed autopower spectrum (0.39Hz). Therefore, segments of spike trains with a signal-to-noise ratio ≥2 at 0.39Hz were termed dystonia frequency (DF) segments, which occurred more commonly during dystonia related to movement. Those with a SNR<2 were termed non-dystonia frequency (nDF) segments, which were associated with spontaneous dystonia. We concentrated on nDF activity since neuronal activity in our controls was measured at rest. Neuronal spike trains were categorized into those with post-inhibitory bursts (G, grouped), with single spikes (NG, non-grouped), or with both single spikes and bursts (I, intermediate). nDF spike trains in ventral oral had more G category firing in dystonia than in controls. The burst rate and the pre-burst silent period in nDF firing of organic dystonia were consistently greater than those of both the monkeys and the patient with Psyd. The distribution of the pre-burst silent period was bimodal with a longer mode of approximately GABAb (gamma amino butyric acid receptor-type b) duration. These results demonstrate distinct differences of post-inhibitory bursting in organic dystonia versus controls. The presence of inhibitory events consistent with GABAb duration suggests interventions for treatment of dystonia.

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.

Thalamic physiology of intentional essential tremor is more like cerebellar tremor than postural essential tremor.

The neuronal physiological correlates of clinical heterogeneity in human essential tremor are unknown. We now test the hypothesis that thalamic neuronal and EMG activities during intention essential tremor are similar to those of the intention tremor which is characteristic of cerebellar lesions. Thalamic neuronal firing was studied in a cerebellar relay nucleus (ventral intermediate, Vim) and in a pallidal relay nucleus (ventral oral posterior, Vop) during stereotactic surgery for the treatment of tremor. Nine patients with essential tremor were divided clinically into two categories: one with a substantial component of tremor with intention (termed intention ET) and the other without (postural ET). These types of essential tremor were compared with patients having intention tremor plus other clinical signs of cerebellar disease (cerebellar tremor). Neurons in patients with either intention ET or cerebellar tremor had lower firing rates and lower spike×EMG coherence than those in patients with postural ET. Patients with intention ET had a lower spike×EMG phase lead than those with postural ET. Overall, thalamic activity measures of intention ET were different from postural ET but not apparently different from those of cerebellar tremor. One patient with the intention ET (number 4) had a good response to a left thalamotomy and then suffered a right cerebellar hemispheric infarct five years later. After the stroke the intention ET recurred, which is consistent with our hypothesis that intention ET is similar to that of the intention tremor which is characteristic of cerebellar lesions.

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.

Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe.

The current model of fear conditioning suggests that it is mediated through modules involving the amygdala (AMY), hippocampus (HIP), and frontal lobe (FL). We now test the hypothesis that habituation and acquisition stages of a fear conditioning protocol are characterized by different event-related causal interactions (ERCs) within and between these modules. The protocol used the painful cutaneous laser as the unconditioned stimulus and ERC was estimated by analysis of local field potentials recorded through electrodes implanted for investigation of epilepsy. During the prestimulus interval of the habituation stage FL>AMY ERC interactions were common. For comparison, in the poststimulus interval of the habituation stage, only a subdivision of the FL (dorsolateral prefrontal cortex, dlPFC) still exerted the FL>AMY ERC interaction (dlFC>AMY). For a further comparison, during the poststimulus interval of the acquisition stage, the dlPFC>AMY interaction persisted and an AMY>FL interaction appeared. In addition to these ERC interactions between modules, the results also show ERC interactions within modules. During the poststimulus interval, HIP>HIP ERC interactions were more common during acquisition, and deep hippocampal contacts exerted causal interactions on superficial contacts, possibly explained by connectivity between the perihippocampal gyrus and the HIP. During the prestimulus interval of the habituation stage, AMY>AMY ERC interactions were commonly found, while interactions between the deep and superficial AMY (indirect pathway) were independent of intervals and stages. These results suggest that the network subserving fear includes distributed or widespread modules, some of which are themselves "local networks." ERC interactions between and within modules can be either static or change dynamically across intervals or stages of fear conditioning.

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.

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

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.

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.

Altered pain and thermal sensation in subjects with isolated parietal and insular cortical lesions.

Studies of sensory function following cortical lesions have often included lesions which multiple cortical, white matter, and thalamic structures. We now test the hypothesis that lesions anatomically constrained to particular insular and parietal structures and their subjacent white matter are associated with different patterns of sensory loss. Sensory loss was measured by quantitative sensory testing (QST), and evaluated statistically within patients relative to normal values. All seven subjects with insular and/or parietal lesions demonstrated thermal hypoesthesia, although the etiology of the lesions was heterogeneous. Cold and heat hypoalgesia were only found in the subject with the most extensive parietal and insular lesion, which occurred in utero. Cold allodynia occurred clinically and by thresholds in two subjects with isolated ischemic lesions of the posterior insular/retroinsular cortex, and by thresholds in two subjects with a lesion of parietal cortex with little or no insular involvement. Central pain occurred in the two subjects with clinical allodynia secondary to isolated lesions of the posterior insular/retroinsular cortex, which spared the anterior and posterior parietal cortex. These results suggest that nonpainful cold and heat sensations are jointly mediated by parietal and insular cortical structures so that lesions anywhere in this system may diminish sensitivity. In contrast, thermal pain is more robust requiring larger cortical lesions of these same structures to produce hypoalgesia. In addition, cold allodynia can result from restricted lesions that also produce thermal hypoesthesia, but not from all such lesions.

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.