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

doi:10.1016/j.neuroscience.2009.11.026

Neuroscience

Volume 165, Issue 4, 17 February 2010, Pages 1402-1411

https://doi.org/10.1016/j.neuroscience.2009.11.026 Get rights and content

Abstract

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.

Section snippets

Experimental procedures

The protocol for these studies was reviewed and approved annually by the Institutional Review Board of Johns Hopkins Medicine. These studies were carried out after implantation of depth electrodes in the amygdala and hippocampus for investigation of medically intractable epilepsy in four subjects (Table 1). All subjects gave written informed consent for participation in these studies. All the techniques used in this study have been previously reported (18). Preoperative evaluation by a

Results

This study was carried out in four subjects with medically intractable CPSz, but not GM seizures (see Table 1). Scalp monitoring suggested the possibility of temporal lobe seizures in all subjects which were further investigated by implantation of depth electrodes in the hippocampus and amygdala. Seizure monitoring was carried out over a 1 week period starting the day after implantation. No subject took medications other than anti-epileptic drugs and these were discontinued for 36 h after the

Discussion

We have tested the hypothesis that the primate amygdala and hippocampus receive inputs arising from nociceptors. The results showed that LEP N2*, P2** and N2P2* were recorded from electrodes implanted in the amygdala and hippocampus. The latencies of these potentials were similar to those recorded from scalp electrodes over the vertex and subdural electrodes over the sylvian fissure (present Table 1, Table 2 in (Lenz et al., 1998a)). The amygdala and hippocampal responses resulted from the

Acknowledgments

This work was supported by the National Institutes of Health—National Institute of Neurological Disorders and Stroke (NS38493 and NS40059 to FAL). We thank L. H. Rowland and J. Winberry for excellent technical assistance.

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Amygdala activation has also been linked to top-down pain modulation through enhanced functional connectivity with the rostral anterior cingulate cortex (Bingel & Tracey, 2008); and there is an evidence for activation of the μ-opioid system in the amygdala detected by radioligand positron emission tomography (PET) during sustained muscle pain induced by infusion of hypertonic saline into the jaw muscle (Zubieta et al., 2005; see also Apkarian et al., 2005). Importantly, electrophysiological studies in patients with epilepsy (Liu et al., 2011) found evidence for a direct nociceptive pathway and an indirect ventral to dorsal pathway to the central nucleus (dorsal region in the human amygdala) by measuring local field potentials in response to thulium-YAG laser-evoked heat pain stimuli (Liu et al., 2010, 2011). These clinical neuroimaging and electrophysiology data validate the results of preclinical work on the pain-related amygdala circuitry processing direct nociceptive input from PB and multimodal thalamocortical input from LA-BLA as discussed earlier (see “Inputs” in “Amygdala neurocircuitry of ‘pain processing’”).
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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 (0–8 Hz) and the Gamma Window (30–55 Hz). Decreased oscillatory power (Event Related Desynchronization – ERD) was found in Alpha (8–14 Hz) and Beta Windows (14–30 Hz). 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.
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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
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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 (8–12 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.
N-methyl-d-aspartate receptor agonism and antagonism within the amygdaloid central nucleus suppresses pain affect: Differential contribution of the ventrolateral periaqueductal gray
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The amygdala contributes to the generation of pain affect, and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study compared the contribution of N-methyl-d-aspartate (NMDA) receptor agonism and antagonism in the CeA to generation of the affective response of rats to an acute noxious stimulus. Vocalizations that occur following a brief tail shock (vocalization afterdischarges) are a validated rodent model of pain affect and were preferentially suppressed, in a dose-dependent manner, by bilateral injection into the CeA of NMDA (.1, .25, .5, or 1 μg/side) or the NMDA receptor antagonist d-(–)-2-amino-5-phosphopentanoic acid (AP5; 1, 2, or 4 μg/side). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of NMDA or AP5 into the CeA. Injection of NMDA, but not AP5, into the CeA increased c-Fos immunoreactivity in the ventrolateral periaqueductal gray, and unilateral injection of the μ-opiate receptor antagonist H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP; .25 μg) into ventrolateral periaqueductal gray prevented the antinociception generated by injection of NMDA into the CeA. These findings demonstrate that although NMDA receptor agonism and antagonism in the CeA produce similar suppression of pain behaviors, they do so via different neurobiologic mechanisms.
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Pain MechanismResearch PaperPainful stimuli evoke potentials recorded from the medial temporal lobe in humans

Abstract

Section snippets

Experimental procedures

Results

Discussion

Acknowledgments

Brain Res

Eur J Pain

Brain Res

Electroencephalogr Clin Neurophysiol

Pain

Prog Neurobiol

Brain Res

Neuron

Neuron

Pain

Brain Res

Pain

Trends Cogn Sci

Pain

Neurosci Lett

Pain

Electroencephalogr Clin Neurophysiol

Neurosci Lett

Brain Res Cogn Brain Res

Neurosci Lett

Int J Psychophysiol

Electroencephalogr Clin Neurophysiol

Neuroscience

Pain

Exp Neurol

Brain Res

Brain Res Rev

Clin Neurophysiol

Neuropharmacology

Pain

Neurobiol Learn Mem

Pain

Brain Res

J Neurosci Methods

Evaluation of specific absorption rate as a dosimeter of MRI-related implant heating

J Magn Reson Imaging

Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study

Magn Reson Med

The control of the false discovery rate under dependency

Ann Stat

The spinotrigeminopontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes

J Neurophysiol

Nucleus centralis of the amygdala and the globus pallidus ventralis: electrophysiological evidence for an involvement in pain processes

J Neurophysiol

Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study

Brain

Accuracy of MRI-guided stereotactic thalamic functional neurosurgery

Neuroradiology

Pain Mechanism
Research Paper
Painful stimuli evoke potentials recorded from the medial temporal lobe in humans