Responses of neurons in rostral ventromedial medulla to nociceptive stimulation of craniofacial region and tail in rats.

The rostral ventromedial medulla (RVM) plays a key role in the endogenous modulation of nociceptive transmission in the central nervous system (CNS). The primary aim of this study was to examine whether the activities of RVM neurons were related to craniofacial nociceptive behaviour (jaw-motor response, JMR) as well as the tail-flick response (TF). The activities of RVM neurons and TF and JMR evoked by noxious heating of the tail or perioral skin were recorded simultaneously in lightly anaesthetized rats. Tail or perioral heating evoked the TF and JMR, and the latency of the JMR was significantly shorter (P < 0.001) than that of the TF. Of 89 neurons recorded in RVM, 40 were classified as ON-cells, 27 as OFF-cells, and 22 as NEUTRAL-cells based on their responsiveness to heating of the tail. Heating at either site caused an increase in ON-cell and decrease in OFF-cell activity before the occurrence of the TF and JMR, but did not alter the activity of NEUTRAL cells. Likewise, noxious stimulation of the temporomandibular joint had similar effects on RVM neurons. These findings reveal that the JMR is a measure of the excitability of trigeminal and spinal nociceptive circuits in the CNS, and that the JMR as well as TF can be used for studying processes related to descending modulation of pain. The findings also support the view that RVM ON- and OFF-cells play an important role in the elaboration of diverse nociceptive behaviours evoked by noxious stimulation of widely separated regions of the body.

Gamma oscillations in the somatosensory thalamus of a patient with a phantom limb: case report.

The amputation of an extremity is commonly followed by phantom sensations that are perceived to originate from the missing limb. The mechanism underlying the generation of these sensations is still not clear although the development of abnormal oscillatory bursting in thalamic neurons may be involved. The theory of thalamocortical dysrhythmia implicates gamma oscillations in phantom pathophysiology although this rhythm has not been previously observed in the phantom limb thalamus. In this study, the authors report the novel observation of widespread 38-Hz gamma oscillatory activity in spike and local field potential recordings obtained from the ventral caudal somatosensory nucleus of the thalamus (Vc) of a phantom limb patient undergoing deep brain stimulation (DBS) surgery. Interestingly, microstimulation near tonically firing cells in the Vc resulted in high-frequency, gamma oscillatory discharges coincident with phantom sensations reported by the patient. Recordings from the somatosensory thalamus of comparator groups (essential tremor and pain) did not reveal the presence of gamma oscillatory activity.

Orofacial proprioceptive thalamus of the rat.

The ascending pathway mediating proprioception from the orofacial region is still not fully known. The present study elucidated the relay of jaw-closing muscle spindle (JCMS) inputs from brainstem to thalamus in rats. We injected an anterograde tracer into the electrophysiologically identified supratrigeminal nucleus (Su5), known to receive JCMS input. Many thalamic axon terminals were labeled and were found mainly contralaterally in a small, unpredicted area of the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM). Electrical stimulation of the masseter nerve and passive jaw movements induced large responses in the VPMcvm. The VPMcvm is far from the rostrodorsal part of ventral posterolateral thalamic nucleus (VPL) where proprioceptive inputs from the body are represented. After injection of a retrograde tracer into the electrophysiologically identified VPMcvm, many neurons were labeled almost exclusively in the contralateral Su5, whereas no labeled neurons were found in the principal sensory trigeminal nucleus (Pr5) and spinal trigeminal nucleus (Sp5). In contrast, after injection of a retrograde tracer into the core of VPM, many neurons were labeled contralaterally in the Pr5 and Sp5, but none in the Su5. We conclude that JCMS input excites trigeminothalamic projection neurons in the Su5 which project primarily to the VPMcvm in marked contrast to other proprioceptors and sensory receptors in the orofacial region which project to the core VPM. These findings suggest that lesions or deep brain stimulation in the human equivalent of VPMcvm may be useful for treatment of movement disorders (e.g., orofacial tremor) without affecting other sensations.

Neural overlap between resting state and self-relevant activity in human subcallosal cingulate cortex--single unit recording in an intracranial study.

High activity of the default mode network (DMN) has been proposed to be central in processing self-relevant events. Thus far, this hypothesis of DMN function has not been tested directly using neurophysiological techniques. To test for the link between frontal midline DMN activity and self-relevant processing we measured neuronal activity (single-neurons' firing rates) in human subcallosal cingulate cortex (SCC) in the course of Deep Brain Stimulation surgery. We find that firing rates in SCC did not change during the presentation of specifically self-relevant stimuli when compared to the preceding pre-stimulus resting state level. In contrast, we observed significant changes in firing rates during other names in SCC. Such rest-self overlap seems to be specific for SCC since increase in firing rates in response to self-relevant stimuli were observed in another region, the subthalamic nucleus, in a group of Parkinson patients receiving deep brain stimulation surgery. These results suggest specific relationship between resting state and self-related activity, rest-self overlap, in specifically SCC as core region of the default-mode network.

Beta oscillatory neurons in the motor thalamus of movement disorder and pain patients.

Excessive beta oscillations (15-25Hz) in the basal ganglia have been linked to the akineto-rigid symptoms of Parkinson's disease (PD) although it remains unclear whether the underlying mechanism is causative or associative. While a number of studies have reported beta activity in the subthalamic nucleus and globus pallidus internus, relatively little is known about the beta rhythm of the motor thalamus and its relation to movement disorders. To test whether thalamic beta oscillations are related to parkinsonian symptoms, we examined the spectral properties of neuronal activity in the ventral thalamic nuclei of five Parkinson's disease patients (two female, age range 50-72years) and compared them to five essential tremor (three female, aged 41-75) and four central pain patients (one female, aged 38-60). Spike and local field potential recordings were obtained during microelectrode-guided localization of thalamic nuclei prior to the implantation of deep brain stimulating electrodes. A total of 118 movement-related neurons in the region of the ventral intermediate nucleus (Vim) were analyzed across all patient groups. Eighty of these neurons (68%) displayed significant oscillatory firing in the beta range with the limbs at rest. In contrast, only 5.7% of the ventral oral posterior (Vop) (χ(2) test, p<0.05) and only 7.2% of the ventral caudal (Vc) neurons fired rhythmically at beta frequency (χ(2) test, p<0.05). Beta power was significantly decreased during limb movements (ANOVA, p<0.05) and was inversely related to tremor-frequency power during tremor epochs in ET and PD (r(2)=0.44). Comparison between patient groups showed that Vim beta power was significantly higher in ET patients versus pain and PD groups (ANOVA, p<0.05). The findings suggest that beta oscillations are found predominantly in Vim and are involved in movement but are not enhanced in tremor-dominant Parkinson's patients.

Response of human thalamic neurons to high-frequency stimulation.

Thalamic deep brain stimulation (DBS) is an effective treatment for tremor, but the mechanisms of action remain unclear. Previous studies of human thalamic neurons to noted transient rebound bursting activity followed by prolonged inhibition after cessation of high frequency extracellular stimulation, and the present study sought to identify the mechanisms underlying this response. Recordings from 13 thalamic neurons exhibiting low threshold spike (LTS) bursting to brief periods of extracellular stimulation were made during surgeries to implant DBS leads in 6 subjects with Parkinson's disease. The response immediately after cessation of stimulation included a short epoch of burst activity, followed by a prolonged period of silence before a return to LTS bursting. A computational model of a population of thalamocortical relay neurons and presynaptic axons terminating on the neurons was used to identify cellular mechanisms of the observed responses. The model included the actions of neuromodulators through inhibition of a non-pertussis toxin sensitive K(+) current (I(KL)), activation of a pertussis toxin sensitive K(+) current (I(KG)), and a shift in the activation curve of the hyperpolarization-activated cation current (I(h)). The model replicated well the measured responses, and the prolonged inhibition was associated most strongly with changes in I(KG) while modulation of I(KL) or I(h) had minimal effects on post-stimulus inhibition suggesting that neuromodulators released in response to high frequency stimulation are responsible for mediating the post-stimulation bursting and subsequent long duration silence of thalamic neurons. The modeling also indicated that the axons of the model neurons responded robustly to suprathreshold stimulation despite the inhibitory effects on the soma. The findings suggest that during DBS the axons of thalamocortical neurons are activated while the cell bodies are inhibited thus blocking the transmission of pathological signals through the network and replacing them with high frequency regular firing.

Nerve resection, crush and re-location relieve complex regional pain syndrome type II: a case report.

This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves.

The gap junction blocker carbenoxolone attenuates nociceptive behavior and medullary dorsal horn central sensitization induced by partial infraorbital nerve transection in rats.

Glial cells are being increasingly implicated in mechanisms underlying pathological pain, and recent studies suggest glial gap junctions involving astrocytes may contribute. The aim of this study was to examine the effect of a gap junction blocker, carbenoxolone (CBX), on medullary dorsal horn (MDH) nociceptive neuronal properties and facial mechanical nociceptive behavior in a rat trigeminal neuropathic pain model involving partial transection of the infraorbital nerve (p-IONX). p-IONX produced facial mechanical hypersensitivity reflected in significantly reduced head withdrawal thresholds that lasted for more than 3weeks. p-IONX also produced central sensitization in MDH nociceptive neurons that was reflected in significantly increased receptive field size, reduction of mechanical activation threshold, and increases in noxious stimulation-evoked responses. Intrathecal CBX treatment significantly attenuated the p-IONX-induced mechanical hypersensitivity and the MDH central sensitization parameters, compared to intrathecal vehicle treatment. These results provide the first documentation that gap junctions may be critically involved in orofacial neuropathic pain mechanisms.

Neuronal coding of implicit emotion categories in the subcallosal cortex in patients with depression.

BACKGROUND: The subcallosal cingulate and adjacent ventromedial prefrontal cortex (collectively referred to here as the subcallosal cortex or SCC) have been identified as key brain areas in emotional processing. The SCC's role in affective valuation as well as severe mood and motivational disturbances, such as major depression, has been largely inferred from measures of neuronal population activity using functional neuroimaging. On the basis of imaging studies, it is unclear whether the SCC predominantly processes 1) negatively valenced affective content, 2) affective arousal, or 3) category-specific affective information. METHODS: To clarify these putative functional roles of the SCC, we measured single neuron activity in the SCC of 15 human subjects undergoing deep brain stimulation for depression while they viewed emotionally evocative images grouped into categories that varied in emotional valence (pleasantness) and arousal. RESULTS: We found that the majority of responsive neurons were modulated by specific emotion categories, rather than by valence or arousal alone. Moreover, although these emotion-category-specific neurons responded to both positive and negative emotion categories, a significant majority were selective for negatively valenced emotional content. CONCLUSIONS: These findings reveal that single SCC neuron activity reflects the automatic valuational processing and implicit emotion categorization of visual stimuli. Furthermore, because of the predominance of neuronal signals in SCC conveying negative affective valuations and the increased activity in this region among depressed people, the effectiveness of depression therapies that alter SCC neuronal activity may relate to the down-regulation of a previously negative emotional processing bias.

Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain.

Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain.

Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model.

UNLABELLED: The aim of this study was to determine whether pregabalin affects nociceptive behavior and central sensitization in a trigeminal neuropathic pain model. A partial infraorbital nerve transection (p-IONX) or sham operation was performed in adult male rats. Nociceptive withdrawal thresholds were tested with von Frey filaments applied to the bilateral vibrissal pads pre- and postoperatively. On postoperative day 7, the behavioral assessment was conducted before and at 30, 60, 120, and 180 minutes after and 24 hours after pregabalin (.1, 1, 10, 100 mg/kg intraperitoneally) or saline injection. The effects of pregabalin or saline were also examined on the mechanoreceptive field and response properties of nociceptive neurons recorded in the medullary dorsal horn at postoperative days 7 to 10. Reduced withdrawal thresholds reflecting bilateral mechanical allodynia were observed in p-IONX rats until postoperative day 28, but not in sham-operated rats. At postoperative day 7, pregabalin significantly and dose-dependently reversed the reduced mechanical withdrawal thresholds in p-IONX rats. Pregabalin also attenuated central sensitization of the neurons, as reflected in reversal of their reduced activation threshold, increased responses to pinch/pressure, and enhanced stimulus-response function. This study provides the first documentation that pregabalin attenuates the mechanical allodynia and central sensitization that characterize this trigeminal neuropathic pain model, and supports its clinical use for treating craniofacial neuropathic pain. PERSPECTIVE: Trigeminal nerve injury in rats produced facial mechanical hypersensitivity and trigeminal central sensitization of medullary dorsal horn neurons that were markedly attenuated by systemically administered pregabalin, suggesting its potential clinical utility for orofacial neuropathic pain.

Spatial extent of ß oscillatory activity in and between the subthalamic nucleus and substantia nigra pars reticulata of Parkinson's disease patients.

Parkinson's disease (PD) is accompanied by a significant amount of ß-band (11 Hz-30 Hz) neuronal and local field potential (LFP) oscillatory activity in the subthalamic nucleus (STN). Previous studies have shown significant coherence between neuronal firing and LFPs at ß frequencies at sites separated by ~1 mm and that the magnitude of ß oscillatory LFP activity and coherence are greatly reduced following levodopa administration. However, these data have been collected from large DBS contact electrodes or pairs of microelectrodes in proximity to each other and so it is not clear whether all regions of STN are synchronized. It is also not known whether the LFP and neuronal activity in the substantia nigra pars reticulata (SNr) shows ß activity and whether it is coherent with STN activity. Therefore, the aim of this study was to measure the spatial extent of ß coherent activity in the STN and coherence between STN and SNr in PD patients OFF levodopa by systematically varying the distance between the dual microelectrodes. A total of 170 pairs of recordings were collected from 20 patients at rest undergoing DBS-STN implantation surgery. Trajectories passed dorsoventrally through STN and into SNr using two microelectrodes initially ~1mm apart. Once the microelectrodes entered the dorsal STN, one of the two was held stationary, while the other one was advanced into SNr over a distance of ~4-6mm. Pairs of recordings were obtained from STN/STN (n=111), STN/SNr (n=42), and SNr/SNr (n=17). We confirmed previous reports of a progressive attenuation in ß power as electrodes were driven from dorsal to ventral STN and into SNr. Furthermore, we found significant ß-LFP coherence across the dorsoventral extent of STN. Detailed analysis suggested that at least some of the ventral STN and SNr beta activity was locally generated rather than arising from volume conduction from dorsal STN and thus suggests that ß oscillations synchronize both the input and output nuclei of the basal ganglia.

Involvement of ATP in noxious stimulus-evoked release of glutamate in rat medullary dorsal horn: a microdialysis study.

Our electrophysiological studies have shown that both purinergic and glutamatergic receptors are involved in central sensitization of nociceptive neurons in the medullary dorsal horn (MDH). Here we assessed the effects of intrathecal administration of apyrase (a nucleotide degrading enzyme of endogenous adenosine 5-triphosphate [ATP]), a combination of apyrase and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an adenosine A1 receptor antagonist), or 2,3-O-2,4,6-trinitrophenyl-adenosine triphosphate (TNP-ATP, a P2X1, P2X3, P2X2/3 receptor antagonist) on the release of glutamate in the rat MDH evoked by application of mustard oil (MO) to the molar tooth pulp. In vivo microdialysis was used to dialyse the MDH every 5 min, and included 3 basal samples, 6 samples after drug treatment and 12 samples following application of MO. Tooth pulp application of MO induced a significant increase in glutamate release in the MDH. Superfusion of apyrase or TNP-ATP alone significantly reduced the MO-induced glutamate release in the MDH, as compared to vehicle. Furthermore, the suppressive effects of apyrase on glutamate release were reduced by combining it with DPCPX. This study demonstrates that application of an inflammatory irritant to the tooth pulp induces glutamate release in the rat MDH in vivo that may be reduced by processes involving endogenous ATP and adenosine.

Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation.

BACKGROUND: Pedunculopontine nucleus (PPN) DBS has emerged as a potential intervention for patients with gait and balance disorders. However, targeting this nucleus can be challenging. We report on the first neuropathological analyses after PPN-DBS surgery in advanced progressive supranuclear palsy (PSP). METHODS: Two patients with PSP underwent unilateral PPN-DBS surgery and were clinically followed to autopsy. Both patients underwent postmortem neuropathological analysis, including choline acetyltransferase immunohistochemistry, to ascertain PPN boundaries and electrode location. RESULTS: Both patients experienced partial improvement in some motor and nonmotor domains postintervention, but died shortly of other complications. Postmortem neuropathological analysis of each patient confirmed the electrode in a region of cholinergic neuronal loss corresponding to the PPN. CONCLUSIONS: We provide histopathological evidence for the validity of our stereotactic approach to target the PPN and correlate electrode location with clinical outcomes.

Activation of peripheral P2X receptors is sufficient to induce central sensitization in rat medullary dorsal horn nociceptive neurons.

Central sensitization and purinergic receptor mechanisms have been implicated as important processes in acute and chronic pain conditions following injury or inflammation of peripheral tissues. This study has documented that application of the P2X(1,2/3,3) receptor agonist αß-meATP (100mM) to the rat tooth pulp induces central sensitization in medullary dorsal horn nociceptive neurons that is reflected in significant increases in mechanoreceptive field size and responses to noxious stimuli and decreased mechanical activation threshold. Furthermore, these responses can be blocked by pulp application of the P2X(1,2/3,3) antagonist TNP-ATP and also attenuated by medullary application of TNP-ATP. These results suggest that activation of P2X(1,2/3,3) receptors in orofacial tissues plays a critical role in producing central sensitization in medullary dorsal horn nociceptive neurons.

Frequency-dependent effects of electrical stimulation in the globus pallidus of dystonia patients.

Deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been shown to improve dystonia, a movement disorder of repetitive twisting movements and postures. DBS at frequencies above 60 Hz improves dystonia, but the mechanisms underlying this frequency dependence are unclear. In patients undergoing dual-microelectrode mapping of the GPi, microstimulation has been shown to reduce neuronal firing, presumably due to synaptic GABA release. This study examined the effects of different microstimulation frequencies (1-100 Hz) and train length (0.5-20 s), with and without prior high-frequency stimulation (HFS) on neuronal firing and evoked field potentials (fEPs) in 13 dystonia patients. Pre-HFS, the average firing decreased as stimulation frequency increased and was silenced above 50 Hz. The average fEP amplitudes increased up to frequencies of 20-30 Hz but then declined and at 50 Hz, were only at 75% of baseline. In some cases, short latency fiber volleys and antidromic-like spikes were observed and followed high frequencies. Post-HFS, overall firing was reduced compared with pre-HFS, and the fEP amplitudes were enhanced at low frequencies, providing evidence of inhibitory synaptic plasticity in the GPi. In a patient with DBS electrodes already implanted in the GPi, recordings from four neurons in the subthalamic nucleus showed almost complete inhibition of firing with clinically effective but not clinically ineffective stimulation parameters. These data provide additional support for the hypothesis of stimulation-evoked GABA release from afferent synaptic terminals and reduction of neuronal firing during DBS and additionally, implicate excitation of GPi axon fibers and neurons and enhancement of inhibitory synaptic transmission by high-frequency GPi DBS as additional putative mechanisms underlying the clinical benefits of DBS in dystonia.

Oscillatory activity in the globus pallidus internus: comparison between Parkinson's disease and dystonia.

OBJECTIVE: Deep brain stimulation in the globus pallidus internus (GPi) is used to alleviate the motor symptoms of both Parkinson's disease (PD) and dystonia. We tested the hypothesis that PD and dystonia are characterized by different temporal patterns of synchronized oscillations in the GPi, and that the dopaminergic loss in PD makes the basal ganglia more susceptible to oscillatory activity. METHODS: Neuronal firing and local field potentials (LFPs) were simultaneously recorded from the GPi in four PD patients and seven dystonia patients using two independently driven microelectrodes. RESULTS: In the PD patients, beta (11-30 Hz) oscillations were observed in the LFPs and the firing activity of ∼30% of the neurons was significantly coherent with the LFP. However, in the dystonia group, the peak frequency of LFP oscillations was lower (8-20 Hz) and there was a significantly smaller proportion of neurons (∼10%) firing in coherence with the LFP (P<0.001). CONCLUSIONS: These findings suggest that synchronization of neuronal firing with LFP oscillations is a more prominent feature in PD than in dystonia. SIGNIFICANCE: This study adds to the growing evidence that dopaminergic loss in PD may increase the sensitivity of the basal ganglia network to rhythmic oscillatory inputs.