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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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

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.

Background: The application to the skin of spatially interlaced innocuous warm (40 °C) and cool (20 °C) thermodes (termed a thermal grill--TG) can produce an unusual thermal percept, but the mechanisms remain unclear., Methods: We compared the percept quality and intensity over a 120-s period evoked by each of three configurations of a 6-bar thermal stimulator (6 TS): all 40 °C(WARM); all 20 °C(COOL); alternating bars 40/20 °C (TG) at two body sites (forearm and palm)., Results: Both unpleasantness and pain were significantly greater for the TG-induced (vs. either COOL- or WARM-induced) percept. Unpleasantness ratings were significantly higher than pain intensity ratings. Several emotional qualitative descriptors were unique to the TG-induced percept. TG palmar (vs. forearm) stimulation produced a more intense percept and was perceived as painful in more subjects. Temporal profiles of intensities of TG-induced percepts differed from those induced by the COOL or WARM thermodes alone. For both unpleasantness and pain, the site differences in the temporal profile were also unique for TG versus the COOL- or WARM-evoked percepts. Qualitative characteristics of the TG-induced percept varied over time and between subjects., Conclusions: The TG percept intensity and temporal profile were different from those evoked by either of its component parts. The perceived quality is person-specific. These differences suggest that the classic 'TG illusion' results from complex central integration of several types of peripheral afferent inputs activated by the TG. Differing body site-related roles of thermosensory afferents in discrimination versus temperature homeostasis may explain site-related variations in the percept., (© 2014 European Pain Federation - EFIC®)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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., (© 2013 Society of Biological Psychiatry.)

Parkinson's disease (PD) is accompanied by a significant amount of β-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 β frequencies at sites separated by ~1 mm and that the magnitude of β 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 β activity and whether it is coherent with STN activity. Therefore, the aim of this study was to measure the spatial extent of β 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 β power as electrodes were driven from dorsal to ventral STN and into SNr. Furthermore, we found significant β-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 β oscillations synchronize both the input and output nuclei of the basal ganglia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Decreased inhibition and aberrant plasticity are key features in the pathophysiology of dystonia. Impaired short interval cortical inhibition and resultant increased excitability have been described for various forms of dystonia using paired pulse methods with transcranial magnetic stimulation of motor cortex. It is hypothesized that, in addition to cortical abnormalities, impairments in basal ganglia function may lead to dystonia but a deficit of inhibition within the basal ganglia has not been demonstrated to date. To examine the possibility that impaired inhibition and synaptic plasticity within the basal ganglia play a role in dystonia, the present study used a pair of microelectrodes to test paired pulse inhibition in the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) of dystonia and PD patients undergoing implantation of deep brain stimulating (DBS) electrodes. We found that there was less paired pulse depression of local field evoked potentials in the basal ganglia output nuclei of dystonia patients compared with Parkinson's disease patients on dopaminergic medication. Paired pulse depression could be restored following focal high frequency stimulation (HFS). These findings suggest that abnormalities exist in synaptic function of striatopallidal and/or striatonigral terminals in dystonia patients and that these abnormalities may contribute to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. These findings also suggest that HFS is capable of enhancing striatopallidal and striatonigral GABA release in basal ganglia output nuclei, indicating a possible mechanism for the therapeutic benefits of DBS in the GPi of dystonia patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.

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 αβ-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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Movement Disorder Society.)

Our previous studies have demonstrated that application of inflammatory irritant mustard oil (MO) to the tooth pulp induces medullary glutamate release and central sensitization in the rat medullary dorsal horn (MDH), as well as nociceptive sensorimotor responses in craniofacial muscles in rats. There is recent evidence that anticonvulsant drugs such as pregabalin that influence glutamatergic neurotransmission are effective in several pain states. The aim of this study was to examine whether systemic administration of pregabalin attenuated glutamate release in the medulla as well as these nociceptive effects reflected in increased electromyographic (EMG) activity induced by MO application to the tooth pulp. Male adult rats were anesthetized with isofluorane (1.0-1.2%), and jaw and tongue muscle EMG activities were recorded by needle electrodes inserted bilaterally into masseter and anterior digastric muscles and into the genioglossus muscle, and also the medullary release of glutamate was assessed by in vivo microdialysis. Pregabalin or vehicle control (isotonic saline) was administered 30 min before the pulpal application of MO or vehicle control (mineral oil). Application of mineral oil to the maxillary first molar tooth pulp produced no change in baseline EMG activity and glutamate release. However, application of MO to the pulp significantly increased both the medullary release of glutamate and EMG activity in the jaw and tongue muscles for several minutes. In contrast, pre-medication with pregabalin, but not vehicle control, significantly and dose-dependently attenuated the medullary glutamate release and EMG activity in these muscles after MO application to the tooth pulp (analysis of variance (ANOVA), p<0.05). These results suggest that pregabalin may attenuate the medullary release of glutamate and associated nociceptive sensorimotor responses in this acute inflammatory pulpal pain model, and that it may prove useful for the treatment of orofacial inflammatory pain states., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Our understanding of the pathophysiology of movement disorders and associated changes in basal ganglia activities has significantly changed during the last few decades. This process began with the development of detailed anatomical models of the basal ganglia, followed by studies of basal ganglia activity patterns in animal models of common movement disorders and electrophysiological recordings in movement disorder patients undergoing functional neurosurgical procedures. These investigations first resulted in an appreciation of global activity changes in the basal ganglia in parkinsonism and other disorders, and later in the detailed description of pathological basal ganglia activity patterns, specifically burst patterns and oscillatory synchronous discharge of basal ganglia neurons. In this review, we critically summarize our current knowledge of the pathological discharge patterns of basal ganglia neurons in Parkinson's disease, dystonia, and dyskinesias., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model., (Copyright © 2011 IBRO. All rights reserved.)

Previous studies indicate that the astroglial glutamate-glutamine shuttle may be involved in acute pulpal inflammatory pain by influencing central sensitization induced in nociceptive neurons in the trigeminal subnucleus caudalis [the medullary dorsal horn (MDH)] by application of an inflammatory irritant to the rat tooth pulp. The aim of this study was to test if intrathecal application to the rat medulla of the astroglial glutamine synthetase inhibitor methionine sulfoximine (MSO) can influence the central sensitization of MDH nociceptive neurons and the animal's associated behaviour that are manifested in a model of chronic pulpitis pain induced by exposure of a mandibular molar pulp. This model was found to be associated with nocifensive behaviour and enhanced reflex activity evoked by mechanical stimulation of the rat's facial skin and with immunocytochemical evidence of astroglial activation in the MDH. These features were apparent for up to 28 days post-operatively. During this post-operative period, the nocifensive behaviour and enhanced reflex activity were significantly attenuated by intrathecal application of MSO (5 μL, 10 mM) but not by vehicle application. In electrophysiological recordings of nociceptive neuronal activity in the MDH, central sensitization was also evident in pulp-exposed rats but not in intact rats and could be significantly attenuated by MSO application but not by vehicle application. These behavioural and neuronal findings suggest that the astroglial glutamate-glutamine shuttle is responsible for the maintenance of inflammation-induced nocifensive behavioural changes and the accompanying central sensitization in MDH nociceptive neurons in this chronic pulpitis pain model., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Several acute and chronic pain conditions in the face or mouth are very common, and some are unique to the orofacial region. However, the etiology and pathogenesis of most orofacial chronic pain conditions are unresolved, and they are difficult to diagnose and manage. This article provides a brief overview of the neural mechanisms underlying orofacial pain and then highlights recent findings indicating that nonneural cells, specifically satellite cells in the sensory ganglia and astroglia and microglia cells in the central nervous system, are important players in both acute and chronic inflammatory and neuropathic orofacial pain conditions and may offer new targets for management of these conditions.

Bilateral deep brain stimulation of the globus pallidus pars interna (GPi) is the favored neuromodulation procedure in cases of cervical dystonia. The authors report on a case of unilateral GPi implantation that resulted in sustained benefit with marked improvement in pain and dystonia.

Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 neurons was recorded prior to, during, and following systemic administration of the dopamine agonist apomorphine at clinically effective doses. Apomorphine induced a decrease in entropy measured in the inter-spike intervals of sub-thalamic neurons in 6 of the 8 neurons. This is the first report that anti-parkinsonian drugs affect non-linear features of neuronal firing in the basal ganglia of parkinsonian patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Tremor is an important cause of disability in patients with multiple sclerosis (MS). Deep brain stimulation (DBS) in the ventral intermediate nucleus (VIM) of the thalamus is said to be beneficial for MS tremor., Objective: To assess the long-term efficacy of VIM DBS for MS disabling tumor., Methods: We treated 10 patients (4 men and 6 women) with advanced MS-related medication-resistant tremor with DBS at the VIM thalamic nucleus. DBS was unilateral in 9 patients and bilateral in 1 patient in 2 stages. Contralateral arm tremor was assessed with the Fahn-Tolosa-Marin tremor rating scale., Results: At 1 year, 5 of 10 patients (5 of 11 hemispheres) had a reduction in tremor scores with stimulation compared with baseline; in 3 patients, the reduction was > 50%. After 36 months, 3 patients continued benefiting from stimulation, 2 having > 50% improvement. Of the 6 symptomatic sides that did not benefit at 1 year, 3 failed to have even initial benefit, and 3 had a transient improvement lasting < 1 year. One patient stopped using stimulation because of a lack of improvement at 5 months after surgery and was lost to follow-up., Conclusion: Approximately one-half of the patients derived some benefit from VIM DBS 1 year after surgery, but this benefit reached a > 50% reduction in only 30% of the patients. This level of improvement may be related to the variability of the demyelinating lesions and the superimposition of ataxia in the MS patients. Developing better treatments for MS tremor continues to be a challenge.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism (MSA-P), cerebellar and autonomic deficits. In Parkinson's disease (PD), an impaired modulation of motor cortical mu and beta range oscillations may be related to the pathophysiology of bradykinesia. Event-related desynchronization (ERD) of these oscillations occur for 1-2 s preceding a voluntary movement in normal subjects and patients with PD treated with levodopa while only lasting around 0.5 s in untreated patients. Motor cortical rhythms were recorded from subdural strip electrodes in three patients with MSA-P while taking their regular dopaminergic medications. Following a ready cue, patients performed an externally cued wrist extension movement to a go cue. In addition, recordings were obtained during imagined wrist extension movements to the same cues and during self-paced wrist extensions. ERD and event-related synchronization were examined in subject-specific frequency bands. All patients showed movement-related ERD in subject-specific frequency bands below ~40 Hz in both externally cued and self-paced conditions. Preparatory ERD latency preceding self-cued movement was 900 ms in one patient and at or after movement onset in the other two patients. In the externally cued task, a short lasting (<1.3 s) ready cue-related ERD that was not sustained to movement onset was observed in two patients. Imagined movements resulted in go cue-related ERD with a smaller magnitude in the same two patients. These results indicate that the modulation of motor cortical oscillations in patients with MSA that are treated with levodopa is similar to that occurring in untreated patients with PD. The findings suggest that cortical activation in patients with MSA is diminished, may be related to pathophysiological changes occurring in the basal ganglia and correlates with the poor clinical response that these patients typically obtain with dopaminergic therapy.

Deep brain stimulation of the basal ganglia and other brain regions has been used successfully to treat a variety of neurological disorders. However, the mechanisms by which it works, remain unclear. In a previous study, we showed that locally delivered single current pulses delivered from a nearby microelectrode are sufficient to inhibit firing in the internal globus pallidus for tens of milliseconds. The GPi and the substantia nigra pars reticulata are the output nuclei of the basal ganglia and share many anatomical and physiological features. The goal of the current study was to examine the after-effects of trains of high-frequency microstimulation on neuronal firing in the GPi of Parkinson's disease and dystonia patients as well as in the SNr of PD patients. Microelectrode recordings and microstimulation were performed in a total of 57 patients during stereotactic surgery. We found that firing in the GPi and SNr is inhibited for several hundreds of milliseconds following the end of a short, 200 Hz high-frequency train delivered through the recording electrode (e.g., on average 618 ms when stimulating in the SNr with a 0.5 s train of 4 microA pulses at 200 Hz). Inhibition duration usually increased with increasing current intensity, train frequency and generally peaked for trains of 1-2 s, while it decreased with increasing train durations. Statistical analysis with general linear models revealed a significant linear relationship between current intensity and inhibition duration in all nuclei and patient groups. There was also a significant relationship between train frequency and inhibition duration in the SNr and GPi of PD patients and between train duration and inhibition duration in the GPi of PD patients. There was no significant difference in inhibition duration across patient groups but the current threshold for inhibition was significantly different in the SNr compared to the GPi. The characteristics of the inhibition observed are consistent with stimulation-induced GABA release following activation of the GABAergic afferents in the SNr and GPi. The findings suggest that high-frequency microstimulation of the GPi and SNr depresses local neuronal activity and synaptic transmission, and such mechanisms may contribute to the therapeutic effects of DBS.

Release of inflammatory pain mediators from peripheral sensory afferent endings contributes to the development of a positive feedback cycle resulting in chronic inflammation and pain. Botulinum neurotoxin type A (BoNT-A) blocks exocytosis of neurotransmitters and may therefore block the release of pain modulators in the periphery. Subcutaneous administration of BoNT-A (2.5, 5 and 10U) reduced plasma extravasation (PE) caused by electrical stimulation of the saphenous nerve or capsaicin in the rat hindpaw skin (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A also reduced blood flow changes evoked by saphenous nerve stimulation (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A had no effect on PE induced by local injection of substance P (SP) or vasodilation induced by local CGRP injection. Although BoNT-A is an effective treatment for a wide range of painful conditions, the toxin's large size necessitates that it be injected at numerous sites. We found that a short synthetic peptide (TD-1) can facilitate effective transdermal delivery of BoNT-A through intact skin. Coadministration of TD-1 and BoNT-A to the hindpaw skin resulted in a significant reduction in PE evoked by electrical stimulation. The findings show that BoNT-A can be administered subcutaneously or topically with a novel transdermal delivery peptide to reduce inflammation produced by activating nociceptors in the skin. Peptide-mediated delivery of BoNT-A is an easy and non-invasive way of administering the toxin that may prove to be useful in clinical practice., (Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Central sensitization is a fundamental mechanism contributing to acute and chronic pain conditions. Our previous studies have documented a glutamatergic, purinergic and glial-dependent central sensitization that can be induced in rat medullary dorsal horn nociceptive neurons by mustard oil application to the tooth pulp. This study showed that carbenoxolone, a potent gap junction and hemichannel blocker, completely blocked all parameters of mustard oil-induced central sensitization tested in functionally identified medullary dorsal horn nociceptive neurons. These results represent the first evidence suggesting that gap junctions and hemichannels may have a critical role in mediating central sensitization in dorsal horn nociceptive neurons and may account for the spread as well as development of central sensitization.

Despite improvements in anatomic imaging of the basal ganglia, microelectrode recording is still an invaluable tool in locating appropriate targets for neurosurgical intervention. These recording also provide an unparalleled opportunity to study the pathophysiological aspects of diseases. This article reviews the principles of microelectrode recording in functional neurosurgery and discusses the pathologic neurophysiologic findings commonly encountered. It also highlights some of the potential mechanisms of action of both dopaminergic drugs and deep brain stimulation. In addition we review the recent work on pedunculopontine nucleus neurophysiology and trials of deep brain stimulation in that region for gait disturbances in Parkinson's disease.

Postural instability and falls are a major source of disability in patients with advanced Parkinson's disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinson's disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinson's Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinson's Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinson's Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinson's disease but that further evaluation of this procedure is required.

In recent years there has been great interest in oscillatory activity in the brain and in the role of pathological oscillations in the basal ganglia in mediating some of the symptoms of Parkinson's disease (PD). In this study, thalamic and subthalamic nucleus local field potentials were intraoperatively recorded from pairs of closely separated microelectrodes in six PD patients ON and OFF dopaminergic medication. Using correlation and coherence analyses, we found high-frequency oscillatory activity in the 110-170 Hz band in thalamus in patients OFF dopamine. These oscillations were significantly reduced after administration of dopamine-replacement therapy. In contrast, activity in the lower frequencies (the theta and beta ranges) was increased. However, in subthalamic nucleus, we observed an increase in high-frequency oscillatory activity (150-200 Hz), and a reduction of the activity in the low-frequency range after levodopa administration. These findings confirm and extend earlier findings suggesting that in PD there are marked changes in basal ganglia oscillatory activity and that these can be reversed after dopaminergic therapy.

Object: The aim of the current study was to examine and compare the aftereffects of local high-frequency microstimulation through the recording electrode on the firing of neurons in the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) in patients undergoing surgery for deep brain stimulation. Deep brain stimulation has been playing an increasing role in the treatment of Parkinson disease, with the subthalamic nucleus (STN) being the preferred implantation target. Changes in cellular activity indicative of the borders of the STN are typically used during surgery to determine the extent of the STN and locate the optimal target, but in some cases borders may be difficult to identify. In this study the authors compared the effects of microstimulation in the SNr and STN. In previous studies they have shown that microstimulation in the internal globus pallidus, which is functionally similar to the SNr, inhibits firing, whereas similar microstimulation in the STN has minimal effect. The presence of inhibition in the SNr but not in the STN could be used as an additional criterion to help identify the location of the border between the STN and SNr., Methods: Dual microelectrode recordings were performed during stereotactic surgery in 4 patients. Well-isolated high-amplitude units were stimulated extracellularly through the recording microelectrode with 0.5-second trains of high frequency (200 Hz) and low current (

The aim of this study was to investigate whether astroglia in the medullary dorsal horn (trigeminal spinal subnucleus caudalis; Vc) may be involved in orofacial neuropathic pain following trigeminal nerve injury. The effects of intrathecal administration of the astroglial aconitase inhibitor sodium fluoroacetate (FA) were tested on Vc astroglial hyperactivity [as revealed by glial fibrillary acid protein (GFAP) labeling], nocifensive behavior, Vc extracellular signal-regulated kinase phosphorylation (pERK), and Vc neuronal activity in inferior alveolar nerve-transected (IANX) rats. Compared with sham-control rats, a significant increase occurred in GFAP-positive cells in ipsilateral Vc at postoperative day 7 in IANX rats, which was prevented following FA administration. FA significantly increased the reduced head withdrawal latency to high-intensity heat stimulation of the maxillary whisker pad skin in IANX rats, although it did not significantly affect the reduced escape threshold to low-intensity mechanical stimulation of the whisker skin in IANX rats. FA also significantly reduced the increased number of pERK-like immunoreactive cells in Vc and the enhanced Vc nociceptive neuronal responses following high-intensity skin stimulation that were documented in IANX rats, and glutamine administration restored the enhanced responses. These various findings provide the first documentation that astroglia is involved in the enhanced nociceptive responses of functionally identified Vc nociceptive neurons and in the associated orofacial hyperalgesia following trigeminal nerve injury.