Effects of ramped-frequency thalamic deep brain stimulation on tremor and activity of modeled neurons

ObjectiveWe conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor.MethodsSeven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation ‘off’, three ramped-frequency stimulation (RFS) trains from 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network.ResultsTemporally patterned 130 → 60 Hz ramped-frequency trains suppressed tremor relative to stimulation ‘off,’ but 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions.ConclusionFrequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism.SignificanceRamping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern.     

Cortical and thalamic components of neocortical kindling-induced epileptogenesis in behaving cats

Kindling is an essential operating paradigm of the nervous system extensively used both as a model of epileptogenesis and neuroplasticity. In a parallel study conducted on chronically implanted non-anesthetized kindled cats, we report the occurrence of long-lasting slow oscillatory patterns (1.5–2 Hz) called outlasting activities (OA) following the acute seizures (AS) induced by cortical stimulation. Here, we asked if OA observed in the neocortex of kindled animals are generated exclusively by the cortical networks or if they also rely on the burst firing of thalamic neurons. We analyzed the electrophysiological patterns of synchronization of cortical EEG (areas 4, 5, 7, 21, 17, 18, 22) and thalamic field (EThG) (ventral posterior lateral nucleus—VPL), and the influence of modulatory systems originating in the pedunculo-pontine tegmentum (PPT) and locus coeruleus (LC) on the discharge pattern of thalamic neurons during OA. Synchrony analysis of field recordings showed that during AS cortical paroxysmal activities preceded thalamic ones, while during OA this sequential order was reversed. During OA thalamic neurons regularly discharged bursts with the frequency of OA. Electrical stimulation of either PPT or LC during OA decreased both the probability of bursts in thalamocortical neurons and the amplitude of OA. Yet, neither of them was able to block completely the expression of OA. Following PPT/LC stimulation the burst firing of thalamocortical neurons was replaced by tonic firing. We conclude that the thalamus is involved in the mechanism of generation of OA but that it does not play an exclusive role.     

Evaluating optimized temporal patterns of spinal cord stimulation (SCS)

BackgroundTemporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain.ObjectiveWe hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation.MethodsUsing a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation. We evaluated the effect of different temporal patterns on individual neurons recorded in the dorsal horn of urethane-anesthetized rats.ResultsThe optimized pattern and 50 Hz CF stimulation produced greater inhibition of spontaneously firing neurons recorded in vivo than random 50 Hz stimulation or a pattern designed intentionally with poor fitness. Spinal Cord Stimulation (SCS) led to significant changes in the firing patterns of recorded units, and stimulation patterns that generated significant inhibition also tended to reduce entropy and regularize the firing patterns of units, suggesting that patterns of dorsal horn neuron activity may be important for pain perception in addition to the firing rate.ConclusionsThese results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.     

Tremor reduction and modeled neural activity during cycling thalamic deep brain stimulation

ObjectiveThe effectiveness of deep brain stimulation (DBS) depends on both the frequency and the temporal pattern of stimulation. We quantified responses to cycling DBS with constant frequency to determine if there was a critical on and/or off time for alleviating tremor.MethodsWe measured postural tremor in 10 subjects with thalamic DBS and quantified neuronal entropy in a network model of Vim thalamic DBS. We tested 12 combinations of cycling on/off times that maintained the same average frequency of 125 Hz, four constant frequency settings, and baseline.ResultsTremor and neural firing pattern entropy decreased as the percent on time increased from 50% to 100%. Cycling with stimulation on for at least 60% of the time was as effective as regular stimulation. All cycling settings reduced the firing pattern entropy of model neurons from the no stimulation condition by regularizing pathological firing patterns, either through synaptically-mediated inhibition or axon excitation.ConclusionsThese results indicate that pauses present in cycling stimulation decreased its effectiveness in suppressing tremor, and that changes in the amount of tremor suppression were strongly correlated with changes in the firing pattern entropy of model neurons.SignificanceCycling stimulation may reduce power consumption during clinical DBS, and thereby increase the battery life of the implanted pulse generator.     

A Prospective,Randomized Single-Blind Crossover Study Comparing High-Frequency 10,000 Hz and Burst Spinal Cord Stimulation

ObjectivesAlthough both high-frequency and burst spinal cord stimulation (SCS) have shown improved efficacy and patient satisfaction compared with conventional tonic stimulation, there are limited data directly comparing the two. This study aimed to compare both high-frequency 10,000 Hz and burst SCS in the same patients in terms of pain relief and satisfaction in those with axial back pain with or without leg pain.Materials and MethodsThis prospective, single-blind, randomized controlled trial was conducted at an outpatient pain clinic within an academic medical center. Participants were randomly allocated to one of two groups in which they trialed either burst or high-frequency 10,000 Hz SCS over five days, followed by a 24- to 48-hour washout period with no stimulation, and the alternative therapy over the remaining four days. Visual analog scale (VAS) scores were collected immediately before and after both therapy trials. Secondary end points included percentage change in VAS score and patient preference.ResultsOf 25 participants, those receiving burst followed by high-frequency SCS (n = 11) had a mean VAS difference of 4.73 after the first trial period and 2.86 after the second. Of those receiving high-frequency followed by burst SCS (n = 14), mean VAS difference after the first trial period was 4.00 and 1.93 after the second trial period. Four participants were withdrawn owing to lead migration. Both therapies showed statistically significant differences in pre- minus post-VAS scores and percent relief. There were no significant differences in carryover or treatment effects between the two groups. There was a statistically significant association between trial sequence and stimulator type implanted because the first stimulator trialed was more likely to be chosen.ConclusionsThere were no observed differences in VAS pain score decrease when comparing burst and high-frequency 10,000 Hz SCS programming therapies. Patient preference followed an order effect, favoring the first programming therapy in the trial sequence.     

Analgesic Effects of Tonic and Burst Dorsal Root Ganglion Stimulation in Rats With Painful Tibial Nerve Injury

ObjectivesDorsal root ganglion (DRG) stimulation is effective in treating chronic pain. While burst stimulation has been proven to enhance the therapeutic efficacy in spinal cord stimulation, currently only a tonic stimulation waveform is clinically used in DRG stimulation. We hypothesized that burst DRG stimulation might also produce analgesic effect in a preclinical neuropathic pain model. We evaluated both the therapeutic effects of burst DRG stimulation and the possible effects of DRG stimulation upon inflammation within the DRG in a preclinical neuropathic pain model.Materials and MethodsRats received either a painful tibial nerve injury or sham surgery. Analgesic effects of DRG stimulation were evaluated by testing a battery of evoked pain-related behaviors as well as measuring the positive affective state associated with relief of spontaneous pain using conditioned place preference. Histological evidence for neuronal trauma or neuroinflammation was evaluated.ResultsAll of the waveforms tested (20 Hz-tonic, 20 Hz-burst, and 40 Hz-burst) have similar analgesic effects in sensory tests and conditioned place preference. Long-term DRG stimulation for two weeks does not change DRG expression of markers for nerve injury and neuroinflammation.ConclusionsDRG stimulation using burst waveform might be also suitable for treating neuropathic pain.     

Analgesic Effects of Repetitive Transcranial Magnetic Stimulation at Different Stimulus Parameters for Neuropathic Pain: A Randomized Study

ObjectivesThe aim of the present study was to investigate the analgesic effects of repetitive transcranial magnetic stimulation over the primary motor cortex (M1-rTMS) using different stimulation parameters to explore the optimal stimulus condition for treating neuropathic pain.Materials and MethodsWe conducted a randomized, blinded, crossover exploratory study. Four single sessions of M1-rTMS at different parameters were administered in random order. The tested stimulation conditions were as follows: 5-Hz with 500 pulses per session, 10-Hz with 500 pulses per session, 10-Hz with 2000 pulses per session, and sham stimulation. Analgesic effects were assessed by determining the visual analog scale (VAS) pain intensity score and Short-Form McGill Pain Questionnaire 2 (SF-MPQ2) score immediately before and immediately after intervention.ResultsWe enrolled 22 adults (age: 59.8 ± 12.1 years) with intractable neuropathic pain. Linear-effects models showed significant effects of the stimulation condition on changes in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.01). Tukey multiple comparison tests revealed that 10-Hz rTMS with 2000 pulses provided better pain relief than sham stimulation, with greater decreases in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.02).ConclusionsThe results of this study suggest that high-dose stimulation (specifically, 10-Hz rTMS at 2000 pulses) is more effective than lower-dose stimulation for treating neuropathic pain.     

Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain

ObjectiveTo assess the modulation of acute provoked pain by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic neuropathic pain.MethodsIn 32 patients with chronic neuropathic pain affecting one upper limb, laser-evoked potentials (LEPs) (N2 and P2 components) were recorded in response to laser stimulation of the painful or painless hand, before and after active or sham rTMS applied at 10 Hz over the motor cortex corresponding to the painful hand. Laser-induced pain was scored on a visual analogue scale.ResultsBoth active and sham rTMS reduced N2–P2 amplitude of the LEPs in response to painful or painless hand stimulation, likely due to the decline of attention during the sessions. However, active rTMS, but not sham rTMS, specifically reduced N2 amplitude and N2/P2 amplitude ratio of the painful hand LEPs. Painful hand LEP attenuation correlated with the magnitude of pain relief produced by active rTMS.ConclusionMotor cortex rTMS delivered at high frequency (10 Hz) was able to reduce LEP amplitude in parallel with laser-induced pain scores in patients with chronic neuropathic pain. The preferential change in the N2 component suggested a modulation of the sensori-discriminative aspect of laser-induced pain.SignificancePrevious studies have shown that rTMS delivered to various cortical targets by different protocols could modulate experimental pain, primarily in healthy subjects. The present results demonstrate the ability of motor cortex rTMS to interfere with the processing of acute provoked pain, even if there is an underlying chronic neuropathic pain.     

Late-onset thermal hypersensitivity after focal ischemic thalamic infarcts as a model for central post-stroke pain in rats

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that often develops in a delayed manner after thalamic stroke. Here, we describe a new model of CPSP by stereotaxic thalamic injection of endothelin-1. Stroke rats (n=12), but not saline-injected controls (n=12), developed a progressive, contralateral cutaneous thermal hyperalgesia over 4 weeks, without motor deficits. Lesions were highly focal and mainly affected the ventral posterior thalamic complex. Tchis model reproduces the infarct location and delayed hypersensitivity typical of CPSP, and may be useful to investigate its pathophysiology and test therapies targeting recovery and pain after thalamic stroke.     

Pulse Intensity Effects of Burst and Tonic Spinal Cord Stimulation on Neural Responses to Brushing in Patients With Neuropathic Pain

ObjectivesTonic spinal cord stimulation (SCS) is accompanied by paresthesia in affected body regions. Comparatively, the absence of paresthesia with burst SCS suggests different involvement of the dorsal column system conveying afferent impulses from low-threshold mechanoreceptors. This study evaluated cortical activation changes during gentle brushing of a pain-free leg during four SCS pulse intensities to assess the effect of intensity on recruitment of dorsal column system fibers during burst and tonic SCS.Materials and MethodsTwenty patients using SCS (11 burst, nine tonic) for neuropathic leg pain participated. Brushing was administered to a pain-free area of the leg during four SCS intensities: therapeutic (100%), medium (66%), low (33%), and no stimulation. Whole-brain electroencephalography was continuously recorded. Changes in spectral power during brushing were evaluated using the event-related desynchronization (ERD) method in theta (4–7 Hz), alpha (8–13 Hz), and beta (16–24 Hz) frequency bands.ResultsBrushing was accompanied by a suppression of cortical oscillations in the range 4–24 Hz. Stronger intensities of burst and tonic SCS led to less suppression of 4–7 Hz and 8–13 Hz bands in parietal electrodes, and in central electrodes in the 16–24 Hz band, with the strongest, statistically significant suppression at medium intensity. Tonic SCS showed a stronger reduction in 4–7 Hz oscillations over right sensorimotor electrodes, and over right frontal and left sensorimotor electrodes in the 8–13 Hz band, compared to burst SCS.ConclusionsResults suggest that burst and tonic SCS are mediated by both different and shared mechanisms. Attenuated brushing-related ERD with tonic SCS suggests a gating of cortical activation by afferent impulses in the dorsal column, whereas burst may engage different pathways. Diminished brushing-related ERD at medium and therapeutic intensities of burst and tonic SCS points towards a nonlinear effect of SCS on somatosensory processing.     

Dynamic Brain Imaging Response to Spinal Cord Stimulation Differential Frequencies DiFY SCS-PET Clinical Trial

ObjectivesThis study with sequential ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)–computed tomography (CT) scanning was designed to investigate any objective measurable effect of differential frequency stimulation (40 Hz, 4000 Hz, and 10,000 Hz) on specific pain matrix areas in patients who underwent spinal cord stimulation (SCS) for intractable lumbar neuropathic pain.Materials and MethodsIn this single-center, randomized, blinded study, four brain ¹⁸F-FDG PET scans were performed for each patient—at baseline before SCS implant and after 40-Hz, 4000-Hz, and 10,000-Hz stimulation. After 40-Hz stimulation for four weeks, patients were randomized 1:1 (4000 Hz/10,000 Hz), crossing over at another four weeks. ¹⁸F-FDG PET-CT brain scans acquired on the GE-Discovery 710 PET system (GE Healthcare, Chicago, IL) with 128-slice CT (250-MBq dose) were analyzed using the PMOD software (PMOD Technologies Ltd, Zurich, Switzerland). A total of 18 pain regions, the right and left prefrontal cortex (PFC), insula, anterior cingulate cortex (ACC), hippocampus, amygdala, primary somatosensory cortices, secondary somatosensory cortices (SSCII), thalami, parabrachial, and periaqueductal gray (PAG), were analyzed.ResultsA total of 14 patients received 40 Hz for four weeks before crossing over to 10,000 Hz/4000 Hz. A total of 57 PET-CT scans (15 for baseline and 14 each for 40 Hz, 4000 Hz, and 10,000 Hz) were analyzed for maximum standardized uptake value (SUVmax), with a statistically significant difference in SUVmax between 40 Hz and baseline (p = 0.002) and 4000 Hz and baseline (p = 0.001) when pooled across 18 pain matrices. There was no statistical difference in SUVmax between 10,000 Hz and baseline. The pooled analysis showed a proportionately higher thalamic region reduction (59.5%) in metabolic activity than other pain matrices, PFC (52%), insula (50%), ACC (52%), SSCII (49%), and PAG (52%).ConclusionThis large cohort of brain PET scans (n = 57) shows statistically significant differences in brain metabolic activity at 40 Hz and 4000 Hz from baseline, with effect on both nociceptive and affect-cognitive pathways (proportionately higher reduction in the thalamus), highlighting the possible mechanism of SCS.Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT03716557.     

Hyper-excitability in low threshold mechanical A fibers is potentially involved in scorpion BmK sting pain

In the present study, using the single fiber recording technique, we found that BmK I, the main toxic component in scorpion Buthus martensi Karsch (BmK) venom, induced dramatic increase in excitability of rapidly adapting (RA) and type I slowly adapting (SAI) low threshold mechanical A fibers of rat. Five micrograms BmK I (691 nmol, in 10 μl saline) administrated to the receptive fields induced spontaneous activity in 80% of RA and SAI fibers, increased the response to 10 g–10 s stimulation at about 20 times and altered the firing pattern to burst mode with maximal NS (number of spikes in burst) averaging from all fibers studied as many as 59. The increase in the excitability of RA and SAI fibers did not recover completely in 2 h.Our finding suggests that the gigantic abnormal activity in low threshold mechanical A fibers is involved in BmK scorpion sting pain, and the experimental model of BmK scorpion sting pain can be used to study A-fiber related central pathway which is important for relief of refractory neuropathic pain likewise.     

REM dream activity of insomnia sufferers: a systematic comparison with good sleepers

Background and ObjectiveThe dream activity of patients with primary insomnia (PI) has rarely been studied, especially using in-laboratory dream collection, although dreams could be linked to their state of hyperarousal and their negative waking experiences. The objective of the study was to compare patients with PI and good sleeper controls (GSCs) in terms of dream recall frequency and dream content.Patients/MethodsPolysomnography was recorded in 12 patients with PI and 12 GSCs (aged between 30 and 45 years) for five consecutive nights. Rapid eye movement (REM) sleep awakenings were enforced on nights 3 and 5 for dream collections.ResultsThe REM dream collections revealed that the groups were similar in terms of dream recall frequency (p ≤ 0.7). With respect to dream content variables, the dreams of GSCs tended to comprise more positive emotions (p = 0.06), whereas the dreams of patients with PI were characterized by more negative elements than positive ones (p = 0.001). Subjectively, GSCs characterized their dreams as being more pleasant and containing more joy, happiness, and vividness (p ≤ 0.03) than patients with PI. Finally, elevated negative dream content was associated with lower sleep efficiencies in insomnia (p = 0.004).ConclusionThese results suggest that less positive emotions and greater negative content characterize the dreams of patients with PI, which is in line with their waking experiences. One potential explanation could be hyperarousal exacerbating presleep negative mentation, thus contributing to poorer sleep quality. The lack of difference in dream recall frequency is most likely due to the forced awakening “dream collection” procedure. The study of dream activity seems a promising avenue for understanding the 24-h experience of insomnia better and exploring the potential benefits of dream management techniques.     

Evaluation of the Efficacy of Musical Vibroacupuncture in Pain Relief: A Randomized Controlled Pilot Study

ObjectivesTo investigate if skin vibration employing consonant frequencies emitted by skin transducers attached to a combination of acupuncture points and according to musical harmony (musical chord) produces more significant pain relief compared to just a single frequency.Materials and MethodsSkin vibrostimulation produced by five electromagnet transducers was applied at five acupoints traditionally used to pain relief and anxiety in 13 pain-free healthy volunteers using the cold pressor test (CPT). The study consisted of three randomized sessions conducted on alternate days, with participants receiving either simultaneous frequencies of 32, 48, and 64 Hz that equate those used in a musical chord, hereby defined as musical vibroacupuncture (MVA), a single frequency of 32 Hz, set as vibroacupuncture (VA) and sham procedure (SP). CPT scores for pain thresholds and pain tolerance were assessed using repeated-measures ANOVAs. Pain intensity was evaluated using a numerical rating scale (NRS), while sensory and affective aspects of pain were rated using the short-form McGill Pain Questionnaire (SF-MPQ) and State-Trait Anxiety Inventory (STAI) Y-Form.ResultsPain thresholds did not vary significantly between trials. Pain tolerance scores were markedly higher in MVA compared to baseline (p = 0.0043) or SP (p = 0.006) but not for VA. Pain intensity for MVA also differed significantly from the baseline (p = 0.007) or SP (p = 0.027), but not for VA. No significant differences were found in SF-MPQ and STAI questionnaires.ConclusionsThese results suggest that MVA effectively increased pain tolerance and reduced pain intensity when compared with all groups, although not significant to the VA group.     

Supraspinal Effects of Dorsal Root Ganglion Stimulation in Chronic Pain Patients

Objectives: Dorsal root ganglion stimulation (DRGS) has become a popular neuromodulatory treatment for neuropathic pain. We used magnetoencephalography (MEG) to investigate potential biomarkers of pain and pain relief, based on the differences in power spectral density (PSD) during varying degrees of pain and how these oscillations change during DRGS-mediated pain relief.Materials and Methods: Thirteen chronic pain patients with implanted dorsal root ganglion stimulators were included in the MEG analysis. MEG Recordings were performed at rest while the stimulator was turned ON or OFF. Numerical rating scale (NRS) scores were also recorded before and after DRGS was turned OFF and ON. Power spectral and source localization analyses were then performed on preprocessed MEG recordings.Results: With DRGS-OFF, patients in severe pain had significantly increased cortical theta (4–7 Hz) power and decreased cortical alpha (7–13 Hz) power compared to patients reporting less pain. This shift in power toward lower frequencies was contrasted by a shift toward the higher frequency power spectrum (low beta 13–20 Hz activity) during DRGS-mediated pain relief. A significant correlation was found between the increase in low beta activity and the degree of reported pain relief.Conclusion: Our results demonstrate increased low-frequency power spectral activity in chronic pain patients in the absence of stimulation which shifts toward higher frequency power spectrum activity in response to therapeutic DRGS. These cortical changes in response to DRGS provide support for the use of neuroimaging in the search for potential biomarkers of pain.     

Very Low Frequencies Maintain Pain Relief From Dorsal Root Ganglion Stimulation: An Evaluation of Dorsal Root Ganglion Neurostimulation Frequency Tapering

BackgroundDorsal root ganglion neurostimulation (DRG-S) is effective in treating various refractory chronic pain syndromes. In preclinical studies, DRG-S at very low frequencies (<5 Hz) reduces excitatory output in the superficial dorsal horn. Clinically, we have also observed the effectiveness of DRG-S at low frequencies. We conducted a case series to describe the effect of very low-frequency DRG-S stimulation on clinical outcomes.Materials and MethodsDRG-S for refractory low back pain was initiated at parameters consistent with published values. Thereafter, the stimulation frequency of DRG-S was reduced in a stepwise fashion to the lowest frequency that maintained pain relief. Pain intensity, disability, and general health status data were collected at baseline, prior to initiation of tapering, and at four weeks after each patient’s lowest effective stimulation frequency was reached.ResultsAfter device activation (N = 20), DRG-S frequency was tapered from 16 to 4 Hz over a 4- to 17-week period, reducing charge-per-second by nearly two-thirds. Even so, pain relief was maintained at more than 75%, with consistent findings in the other measures.ConclusionDRG-S may have utility in treating chronic pain at lower stimulation frequencies than previously recognized. We have previously theorized that the mechanism of action may involve preferential recruitment of low-threshold mechanoreceptor fibers via the endogenous opioid system. Of clinical relevance, lower frequency stimulation maintains DRG-S efficacy regarding improvements in pain, disability, and quality of life. It can extend battery life and may potentially lead to the development of smaller implantable pulse generators.     

The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain

Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others' has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether this dysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation, we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20 pain‐free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4–25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neurotransmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.     

A Review of Effects of Spinal Cord Stimulation on Spectral Features in Resting-State Electroencephalography

BackgroundSpinal cord stimulation (SCS) is an effective therapy for patients with refractory chronic pain syndromes. Although studies have shown that SCS has both spinal and supraspinal effects, the current understanding of cortical effects is still limited. Neuroimaging techniques, such as magnetoencephalography (MEG) and electroencephalography (EEG), combined here as M/EEG, can reveal modulations in ongoing resting-state cortical activity. We aim to provide an overview of available literature on resting-state M/EEG in patients with chronic pain who have been treated with SCS.Materials and MethodsWe searched multiple online data bases for studies on SCS, chronic pain, and resting-state M/EEG. Primary outcome measures were changes in spectral features, combined with brain regions in which these changes occurred.ResultsWe included eight studies reporting various SCS paradigms (tonic, burst, high-dose, and high-frequency stimulation) and revealing heterogeneity in outcome parameters. We summarized changes in cortical activity in various frequency bands: theta (4–7 Hz), alpha (7–12 Hz), beta (13–30 Hz), and gamma (30–44 Hz). In multiple studies, the somatosensory cortex showed modulation of cortical activity under tonic, burst, and high-frequency stimulation. Changes in connectivity were found in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and parahippocampus.ConclusionsThe large heterogeneity observed in outcome measures is probably caused by the large variety in study designs, stimulation paradigms, and spectral features studied. Paresthesia-free paradigms have been compared with tonic stimulation in multiple studies. These studies suggest modulation of medial, lateral, and descending pathways for paresthesia-free stimulation, whereas tonic stimulation predominantly modulates lateral and descending pathways. Moreover, multiple studies have reported an increased alpha peak frequency, increased alpha power, and/or decreased theta power when SCS was compared with baseline, indicating modulation of thalamocortical pathways. Further studies with well-defined groups of responders and nonresponders to SCS are recommended to independently study the cortical effects of pain relief and SCS.     

Theta-burst versus 20 Hz repetitive transcranial magnetic stimulation in neuropathic pain: A head-to-head comparison

ObjectiveHigh-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent “theta-burst” stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain.MethodsForty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks.ResultsPain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095–3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques.ConclusionsHigh-frequency rTMS appeared superior to iTBS for neuropathic pain relief.SignificanceAdequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation.     

In vivo neuronal firing patterns during human epileptiform discharges replicated by electrical stimulation

ObjectiveTo describe neuronal firing patterns observed during human spontaneous interictal epileptiform discharges (IEDs) and responses to single pulse electrical stimulation (SPES).MethodsActivity of single neurons was recorded during IEDs and after SPES in 11 consecutive patients assessed with depth EEG electrodes and attached microelectrodes.ResultsA total of 66 neurons were recorded during IEDs and 151 during SPES. We have found essentially similar patterns of neuronal firing during IEDs and after SPES, namely: (a) a burst of high frequency firing lasting less than 100 ms (in 39% and 25% of local neurons, respectively for IED and SPES); (b) a period of suppression in firing lasting around 100–1300 ms (in 19% and 14%, respectively); (c) a burst followed by suppression (in 10% and 12%, respectively); (d) no-change (in 32% and 50%, respectively).ConclusionsThe similarities in neuronal firing patterns associated with IEDs and SPES suggest that, although both phenomena are initiated differently, they result in the activation of a common cortical mechanism, probably initiated by brief synchronised burst firing in some cells followed by long inhibition.SignificanceThe findings provide direct in vivo human evidence to further comprehend the pathophysiology of human focal epilepsy.