Spinal cord stimulation improves motor function and gait in spastic paraplegia type 4 (SPG4): Clinical and neurophysiological evaluation

IntroductionHereditary spastic paraplegia is a heterogeneous group of genetic disorders characterized by degeneration of the corticospinal tracts, coursing with progressive weakness and spasticity of the lower limbs. To date, there are no effective treatments for progressive deficits or disease-modifying therapy for those patients. We report encouraging results for spastic paraparesis after spinal cord stimulation.MethodsA 51-year-old woman suffering from progressive weakness and spasticity in lower limbs related to hereditary spastic paraplegia type 4 underwent spinal cord stimulation (SCS) and experienced also significant improvement in motor function. Maximum ballistic voluntary isometric contraction test, continuous passive motion test and gait analysis using a motion-capture system were performed in ON and OFF SCS conditions. Neurophysiologic assessment consisted of obtaining motor evoked potentials in both conditions.ResultsPresurgical Spastic Paraplegia Rating Scale (SPRS) score was 26. One month after effective SCS was initiated, SPRS went down to 15. At 12 months follow up, she experienced substantial improvement in motor function and in gait performance, with SPRS scores 23 (OFF) and down to 20 (ON). There was an increased isometric muscle strength (knee extension, OFF: 41 N m; ON: 71 N m), lower knee extension and flexion torque values in continuous passive motion test (decrease in spastic tone) and improvement in gait (for example, step length increase).ConclusionDespite being a case study, our findings suggest innovative lines of research for the treatment of spastic paraplegia.     

Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation.

To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.     

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.     

Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients

BackgroundThe effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood.ObjectivesBy combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients.MethodsPD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group.ResultsSTN-DBS enhanced early global TMS-evoked activity (∼45–80ms) and high-alpha TMS-evoked oscillations (11–13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80–130ms) and beta TMS-evoked oscillations (13–30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values.ConclusionsOur data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.     

Differences in EEG patterns between tonic and high frequency spinal cord stimulation in chronic pain patients

ObjectiveTo investigate the differences in neural patterns between spinal cord stimulation (SCS) waveforms (60-Hz tonic vs 10-KHz high frequency stimulation, HFS) and their correlation to stimulation-induced pain relief.MethodsWe recorded 10-channel electroencephalogram (EEG) in response to stimulation ON and OFF in 9 chronic pain patients (4 women, 5 men) during SCS surgery and examined the intraoperative spatio-spectral EEG features.ResultsWe discovered stronger relative alpha power in the somatosensory region and higher trend in alpha/theta peak power ratio in frontal cortex with HFS. We also observed a shift in peak frequency from theta to alpha rhythms in HFS as compared to baseline and tonic stimulation, where slower theta activity was maintained. Further, a positive correlation was found between changes in Oswestry disability index (ODI) scores (from preoperative to postoperative) and HFS-induced alpha/theta peak power ratio in frontal and somatosensory regions.ConclusionsAltogether, our findings suggest that dynamic spectral interactions in theta-alpha band and their spatial distributions might be the first intraoperative neural signatures of pain relief induced by HFS in chronic pain.SignificanceExamining electrophysiological changes intraoperatively has a potential to elucidate response to SCS therapy prior to device selection, reducing the healthcare expenditures associated with failed implants.     

Impaired motor cortical facilitatory-inhibitory circuit interaction in Parkinson’s disease

ObjectiveMotor cortical (M1) inhibition and facilitation can be studied with short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). These circuits are altered in Parkinson’s disease (PD). The sensorimotor measure short latency afferent inhibition (SAI) is possibly altered in PD. The aim was to determine if the manner in which these circuits interact with each other is abnormal in PD.MethodsFifteen PD patients were studied at rest in ON and OFF medication states, and were compared to 16 age-matched controls. A triple-stimulus transcranial magnetic stimulation paradigm was used to elicit a circuit of interest in the presence of another circuit.ResultsSICF was increased in PD OFF and PD ON conditions compared to controls. SICI facilitated SICF in controls and PD ON, but not in PD OFF. SICF in the presence of SICI negatively correlated with UPDRS-III scores in OFF and ON medication conditions. SAI showed similar inhibition of SICI in controls, PD OFF and PD ON conditions.ConclusionsThe facilitatory effect of SICI on SICF is absent in PD OFF, but is restored with dopaminergic medication.SignificanceImpaired interaction between M1 circuits is a pathophysiological feature of PD.     

Dissociable dorsal and ventral frontostriatal working memory circuits: Evidence from subthalamic stimulation in Parkinson's disease

In this study, we investigated the neural substrates involved in visual working memory (WM) and the resulting effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD). Cerebral activation revealed by positron emission tomography was compared among Parkinson patients with (PD‐ON) or without (PD‐OFF) STN stimulation, and a group of control subjects (CT) in two visual WM tasks with spatial (SP) and nonspatial (NSP) components. PD‐OFF patients displayed significant reaction time (RT) deficits for both memory tasks. Although there were no significant differences in RT between patients with PD‐ON and ‐OFF stimulation, patients with PD‐ON stimulation performed comparably to controls. The memory tasks were executed with normal error rates in PD‐ON and ‐OFF stimulation. In contrast to these behavioral results, whether the corresponding prefrontal activation was differentially affected by deep brain stimulation status in patients depended on whether the WM modality was SP versus NSP. Thus, SP WM was associated with (1) abnormal reduction in dorsolateral prefrontal activity in PD‐OFF and ‐ON stimulation and (2) abnormal overactivation in parieto‐temporal cortex in PD‐OFF and in limbic circuits in PD‐ON stimulation. In NSP WM, normal activation of the ventral prefrontal cortex was restored in PD‐ON stimulation. In both visual modalities the posterior cerebral regions including fusiform cortex and cerebellum, displayed abnormally reduced activity in PD. These results indicate that PD induces a prefrontal hypoactivation that STN stimulation can partially restore in a modality selective manner by additional recruitment of limbic structures in SP WM or by recovery of the ventral prefrontal activation in NSP WM. Hum Brain Mapp 35:552–566, 2014. © 2012 Wiley Periodicals, Inc.     

Sex,Food and Threat: Startling Changes after Subthalamic Stimulation in Parkinson's Disease

BackgroundChanges in motivational processing may play a role in weight gain and other non-motor side effects in Parkinson's disease (PD) patients treated with deep brain stimulation of the subthalamic nucleus.Objective/hypothesisWe aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli.MethodsABR elicited during the viewing of erotic, food, aversive and neutral pictures was recorded in 11 off-medicated patients with the subthalamic stimulation switched ON and OFF, and in 11 control subjects.ResultsABR to erotic stimuli was larger in patients in the ON compared to the OFF condition and controls (P < 0.01). Aversive stimuli caused a larger increase in the ABR in patients with the ON condition than in controls (P < 0.05). Additionally, we found a negative correlation of the ABR magnitude to food pictures in the ON condition with weight gain following subthalamic stimulation (P < 0.01, after adjustment to OFF condition).ConclusionsOur results suggest that subthalamic stimulation affects motivational processing. Subthalamic stimulation may disturb appetitive engagement by erotic cues and increase aversive activation in PD patients. Additionally, postoperative weight gain may be related to changes in the processing of food cues due to subthalamic stimulation.     

Tonic,Burst, and Burst-Cycle Spinal Cord Stimulation Lead to Differential Brain Activation Patterns as Detected by Functional Magnetic Resonance Imaging

ObjectiveThe objective of this preclinical study was to examine the responses of the brain to noxious stimulation in the presence and absence of different modes of spinal cord stimulation (SCS) using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI).Materials and MethodsSprague-Dawley rats were randomized to groups based on the mode of SCS delivered which included tonic stimulation (n = 27), burst stimulation (n = 30), and burst-cycle stimulation (n = 29). The control (sham) group (n = 28) received no SCS. The SCS electrode was inserted between T10 and T12 spinal levels prior to fMRI session. The experimental protocol for fMRI acquisition consisted of an initial noxious stimulation phase, a treatment phase wherein the SCS was turned on concurrently with noxious stimulation, and a residual effect phase wherein the noxious stimulation alone was turned on. The responses were statistically analyzed through paired t-test and the results were presented as z-scores for the quantitative analysis of the fMRI data.ResultsThe treatment with different SCS modes attenuated the BOLD brain responses to noxious hindlimb stimulation. The tonic, burst, and burst-cycle SCS treatment attenuated BOLD responses in the caudate putamen (CPu), insula (In), and secondary somatosensory cortex (S2). There was little to no corresponding change in sham control in these three regions. The burst and burst-cycle SCS demonstrated greater attenuation of BOLD signals in CPu, In, and S2 compared to tonic stimulation.ConclusionThe high-resolution fMRI study using a rat model demonstrated the potential of different SCS modes to act on several pain-matrix-related regions of the brain in response to noxious stimulation. The burst and burst-cycle SCS exhibited greater brain activity reduction in response to noxious hindlimb stimulation in the caudate putamen, insula, and secondary somatosensory cortex compared to tonic stimulation.     

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.     

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced Parkinson's disease

BackgroundDespite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions.Patients and methodsInvestigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure.ResultsThe comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex.ConclusionDeep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.     

Immediate effects of rhythmic auditory stimulation on gait kinematics in Parkinson’s disease ON/OFF medication

ObjectiveGait impairment is a highly disabling symptom for Parkinson’s disease (PD) patients. Rhythmic auditory stimulation (RAS), has shown to improve spatio-temporal gait parameters in PD, but only a few studies have focused on their effects on gait kinematics, and the ideal stimulation frequency has still not been identified.MethodsWe enrolled 30 PD patients and 18 controls. Patients were evaluated under two conditions (with (ON), and without (OFF) medications) with three different RAS frequencies (90%, 100%, and 110% of the patient’s preferred walking cadence). Spatial-temporal parameters, joint angles and gait phases distribution were evaluated. A novel global index (GPQI) was used to quantify the difference in gait phase distribution.ResultsAlong with benefits in spatial-temporal parameters, GPQI improved significantly with RAS at a frequency of 110% for both ON and OFF medication conditions. In the most severe patients, the same result was observed also with RAS at 100%.ConclusionsRAS administration, at a frequency of 110% of the preferred walking frequency, can be beneficial in improving the gait pattern in PD patients.SignificanceWhen rhythmic auditory stimulation is provided to patients with PD, the selection of an adequate frequency of stimulation can optimize their effects on gait pattern.     

Effects of high-frequency stimulation on epileptiform activity in vitro: ON/OFF control paradigm

Purpose: To determine the effects of high‐frequency electrical stimulation on electrographic seizure activity during and after stimulation (ON‐effect and OFF‐effect). Methods: The modulation and suppression of epileptiform activity during (ON‐effect) and after (OFF‐effect) high‐frequency electrical stimulation was investigated using the high‐K⁺ and picrotoxin hippocampal slice epilepsy models. Uniform sinusoidal fields (50 Hz) were applied with various intensity levels for 1 min across brain slices. Extracellular and intracellular activity were monitored during and after stimulation. Results: The ON‐effects of high‐frequency stimulation were highly variable across individual slices and models; ON‐effects included modulation of activity, pacing, partial suppression, or activity resembling spreading‐depression. On average, epileptic activity, measured as power in the extracellular fields, increased significantly during stimulation. Following the termination of electrical stimulation, a robust poststimulation suppression period was observed. This OFF suppression was observed even at relatively moderate stimulation intensities. The duration of OFF suppression increased with stimulation intensity, independent of ON‐effects. Antagonism of GABA _A function did not directly effect OFF suppression duration. Conclusions: The present results suggest that “rational” seizure control protocols using intermittent high‐frequency electrical stimulation should control for both ON and OFF effects.     

Effects of theta burst stimulation on motor cortex excitability in Parkinson's disease

ObjectiveLong-term potentiation (LTP)-like plasticity induced by paired associative stimulation (PAS) is impaired in Parkinson’s disease (PD). Intermittent theta burst stimulation (iTBS) is another rTMS protocol that produces LTP-like effects and increases cortical excitability but its effects are independent of afferent input. The aim of the present study was to examine the effects of iTBS on cortical excitability in PD.MethodsiTBS was applied to the motor cortex in 10 healthy subjects and 12 PD patients ON and OFF dopaminergic medications. Motor evoked potential (MEP) before and for 60 min after iTBS were used to examine the changes in cortical excitability induced by iTBS. Paired-pulse TMS was used to test whether intracortical circuits, including short interval intracortical inhibition, intracortical facilitation, short and long latency afferent inhibition, were modulated by iTBS.ResultsAfter iTBS, the control, PD ON and OFF groups had similar increases in MEP amplitude compared to baseline over the course of 60 min. Changes in intracortical circuits induced by iTBS were also similar for the different groups.ConclusionsiTBS produced similar effects on cortical excitability for PD patients and controls.SignificanceSpike-timing dependent heterosynaptic LTP-like plasticity induced by PAS may be more impaired in PD than frequency dependent homosynaptic LTP-like plasticity induced by iTBS.     

Gait patterns of a patient with myoclonus of a lower limb,when OFF and ON treatment with antiepileptic drugs

Abstract We describe kinematics, kinetics and electromyographic patterns of a patient with spinal myoclonus of the left lower limb, during walking. Gait analysis was performed when the patient was OFF and ON his treatment with antiepileptic drugs. When OFF, we mainly observed clonic bursts and out-of-phase activations of m. tibialis anterior and m. rectus femoris, with increased hip flexion, reduction of knee flexion during swing and excessive ankle dorsal flexion. Furthermore, large oscillations of knee moment of force and power during stance phase were also observed. These abnormal patterns markedly recovered when ON drugs.     

Comparison of Paresthesia Mapping With Anatomic Placement in Burst Spinal Cord Stimulation: Long-Term Results of the Prospective,Multicenter, Randomized,Double-Blind,Crossover CRISP Study

ObjectivesSpinal cord stimulation (SCS) is an effective therapy for chronic intractable pain. Conventional SCS involves electrode placement based on intraoperative paresthesia mapping; however, newer paradigms like burst may allow for anatomic placement of leads. Here, for the first time, we report the one-year safety and efficacy of burst SCS delivered using a lead placed with conventional, paresthesia mapping, or anatomic placement approach in subjects with chronic low back pain (CLBP).Materials and MethodsSubjects with CLBP were implanted with two leads. The first lead was placed to cross the T8/T9 disc and active contacts for this lead were chosen through paresthesia mapping. The second lead was placed at the T9/T10 spinal anatomic landmark. Subjects initially underwent a four-week, double-blinded, crossover trial with a two-week testing period with burst SCS delivered through each lead in a random order. At the end of trial period, subjects expressed their preference for one of the two leads. Subsequently, subjects received burst SCS with the preferred lead and were followed up at 3, 6, and 12 months. Pain intensity (visual analog scale), quality-of-life (EuroQol-5D instrument), and disability (Oswestry Disability Index) were evaluated at baseline and follow-up.ResultsForty-three subjects successfully completed the trial. Twenty-one preferred the paresthesia mapping lead and 21 preferred the anatomic placement lead. Anatomic placement lead was activated in one subject who had no preference. The pain scores (for back and leg) significantly improved from baseline for both lead placement groups at all follow-up time points, with no significant between-group differences.ConclusionsThis study demonstrated that equivalent clinical benefits could be achieved with burst SCS using either paresthesia mapping or anatomic landmark-based approaches for lead placement. Nonparesthesia-based approaches, such as anatomic landmark-based lead placement investigated here, have the potential to simplify implantation of SCS and improve current surgical practice.     

Evaluating Parkinson's disease patients at home: Utility of self‐videotaping for objective motor,dyskinesia, and ON–OFF assessments

The objective is to test feasibility and utility of home‐based videos for assessing Parkinson's disease (PD) patients. As part of a clinical trial, patients opted between coming to the study sites or learning to videotape assessments at home. Those opting for at‐home filming completed training on videotape techniques. Ten‐minute films were taken at 30‐minute intervals over 8.5 hours, 2 and 4 weeks after study entry using a protocol covering most items of the UDPRS motor examination and all Rush Dyskinesia Rating Scale items. After each filming, patients marked their ON/OFF status, based on prior training. We determined the number of patients who elected self‐taping and the quality of video segments obtained. To assess ON/OFF patient accuracy, we compared the rater's and patient's assessment of ON/OFF at each time point. Of 12 participants, 10 elected self‐videotaping and only 1 time point was missed (99.5% taping compliance). All self‐recorded video segments were clear with all protocol elements included. With the exception of one missed ON/OFF rating, patient‐based self‐ratings occurred on time. Rating ON/OFF, UPDRS, and RDRS assessments for 8.5 hours required 170 minutes by the blinded rater. In spite of patient training, mean ON/OFF concordance between rater and patients was only 64%. At home video‐based self‐recordings are feasible and allow accurate rater‐based ON/OFF assessments. In this group of patients with no or mild fluctuations, in spite of pretrial training, patients were inaccurate in separating ON vs. OFF status. © 2008 Movement Disorder Society     

Nociceptive brain activation in patients with neuropathic pain related to Parkinson's disease

BackgroundPatients suffering from Parkinson's disease (PD) frequently experience painful sensations that may be due to central modification of nociception in PD. We compared pain thresholds and cerebral activity in nociceptive areas using Positron Emission Tomography (PET) during nociceptive stimulation before (OFF condition) and after (ON condition) levodopa challenge between nine PD patients with and nine PD patients without neuropathic pain.MethodsPain thresholds were determined using a cold pressor test in the two conditions. We used H₂¹⁵O PET to study the regional cerebral blood flow changes in subjects while they received alternate randomized noxious and innocuous cold stimuli during OFF and ON periods.ResultsPain thresholds were not significantly different between PD patients with and without pain in either condition (OFF and ON). In both groups of PD patients, levodopa significantly raised pain threshold (F _1,16 = 26.71; p < 0.0001) with a mean variation of ?2.7 (±2.3 °C). In the OFF condition, PD patients with pain had a lower pain activation in the right prefrontal cortex and posterior insula and a higher pain activation in the right anterior cingulate cortex (BA32/8) than pain-free patients. Levodopa significantly reduced pain-induced-activation in the right insula and in the anterior cingulate cortex in both groups.ConclusionLevodopa decreased nociceptive perception in both PD patients with and without pain. In PD patients with neuropathic pain the medial affective pathway was preferentially recruited whereas pain-free PD patients exhibited a greater activation in lateral discriminative nociceptive areas.     

Heterogeneous Cortical Effects of Spinal Cord Stimulation

ObjectivesThe understanding of the cortical effects of spinal cord stimulation (SCS) remains limited. Multiple studies have investigated the effects of SCS in resting-state electroencephalography. However, owing to the large variation in reported outcomes, we aimed to describe the differential cortical responses between two types of SCS and between responders and nonresponders using magnetoencephalography (MEG).Materials and MethodsWe conducted 5-minute resting-state MEG recordings in 25 patients with chronic pain with active SCS in three sessions, each after a one-week exposure to tonic, burst, or sham SCS. We extracted six spectral features from the measured neurophysiological signals: the alpha peak frequency; alpha power ratio (power 7–9 Hz/power 9–11 Hz); and average power in the theta (4–7.5 Hz), alpha (8–12.5 Hz), beta (13–30 Hz), and low-gamma (30.5–60 Hz) frequency bands. We compared these features (using nonparametric permutation t-tests) for MEG sensor and cortical map effects across stimulation paradigms, between participants who reported low (< 5, responders) vs high (≥ 5, nonresponders) pain scores, and in three representative participants.ResultsWe found statistically significant (p < 0.05, false discovery rate corrected) increased MEG sensor signal power below 3 Hz in response to burst SCS compared with tonic and sham SCS. We did not find statistically significant differences (all p > 0.05) between the power spectra of responders and nonresponders. Our data did not show statistically significant differences in the spectral features of interest among the three stimulation paradigms or between responders and nonresponders. These results were confirmed by the MEG cortical maps. However, we did identify certain trends in the MEG source maps for all comparisons and several features, with substantial variation across participants.ConclusionsThe considerable variation in cortical responses to the various SCS treatment options necessitates studies with sample sizes larger than commonly reported in the field and more personalized treatment plans. Studies with a finer stratification between responders and nonresponders are required to advance the knowledge on SCS treatment effects.     

Study of Cerebello-Thalamocortical Pathway by Transcranial Magnetic Stimulation in Parkinson's Disease

BackgroundAlthough functional changes in the activation of the cerebellum in Parkinson's disease (PD) patients have been consistently described, it is still debated whether such altered cerebellar activation is a natural consequence of PD pathophysiology or rather it involves compensatory mechanisms.Objective/HypothesisWe used different forms of cerebellar transcranial magnetic stimulation to evaluate the hypothesis that altered cerebello-cortical interactions can be observed in PD patients and to evaluate the role of dopaminergic treatment.MethodsWe studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with motor-evoked potentials (MEPs) (cerebellar-brain inhibition—CBI) in a group of 16 PD patients with (ON) and without dopaminergic treatment (OFF), and in 16 age-matched healthy controls. Moreover, we also tested the effects of cerebellar continuous theta-burst stimulation (cTBS) on MEP amplitude, short intracortical inhibition (SICI) and short intracortical facilitation (SICF) tested in the contralateral M1 in 13 PD patients in ON and OFF and in 16 age-matched healthy controls.ResultsCBI was evident in controls but not in PD patients, even when tested in both ON and OFF conditions. Similarly, cerebellar cTBS reduced MEP amplitude and SICI in controls but not in PD patients under any condition.Conclusion(s)These results demonstrate that PD patients have deficient short-latency and long-lasting cerebellar-thalamocortical inhibitory interactions that cannot be promptly restored by standard dopaminergic medication.