Low-frequency Stimulation Research Articles

FV 9 Deep Brain Stimulation for targeting tremor and ataxia in SCA 27

Introduction: Spinocerebellar ataxia 27 (SCA 27) is a rare cerebellar ataxia caused by mutations in the FGF14 gene. It is characterised by tremor manifesting in early adulthood and slowly progressive ataxia in later decades. Here, we report the case of a 51 years old male patient who was initially diagnosed with medication-refractory essential tremor and therefore received thalamic deep brain stimulation (DBS). After the patient developed signs of cerebellar ataxia exome sequencing led to the diagnosis of SCA 27. In our clinical practice, we tested stimulation paradigms to target tremor and ataxia inspired by model findings (Anderson et al. 2019) suggesting differential effects of low- and high-frequency stimulation. Methods: The patient was implanted with quadripolar electrodes (model 3389, Medtronic) in the nucleus ventralis intermedius of the thalamus (VIM) with the lowest contact reaching the subthalamic fibre tracts. Initially, stimulation-induced manifestation of cerebellar ataxia was ruled out by a wash-out of DBS for 96 h. Next, we established a high-frequency (180 Hz) programme located at the thalamic contacts achieving best tremor control and a low-frequency (30 Hz) programme located at the lowest contacts to interfere with subthalamic fibre tracts. Electrode placement was verified using Lead-DBS. The Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and the Scale of the Assessment and Rating of Ataxia (SARA) were performed for clinical assessment. At baseline, we evaluated the condition without stimulation (StimOFF) vs. 180 Hz vs. subthalamic 30 Hz stimulation. Further follow-up examinations were scheduled after 5 and 10 weeks. In the meantime, the patient activated the 180 Hz programme at daytime and either StimOff or 30 Hz stimulation at night. The investigator and patient were blinded to the night setting of the previous interval. Results: At baseline, tremor severity was attenuated by 180Hz DBS compared to StimOFF (TRS 13 vs. 21). Tremor was also attenuated by 30 Hz stimulation of the subthalamus at 1 mA (TRS: 14) but was gradually entrained with higher stimulation amplitudes up to 7 mA (TRS: 27). Changes of the SARA where mainly driven by the tremor component. During the first interval period, the patient adopted the 30 Hz night stimulation programme with 4 mA. In the follow-up examination tremor in the StimOFF condition (TRS: 12) improved to a TRS of 7 using the 180 Hz programme. Eventually, after the second period during which the patient adopted StimOFF at night, the baseline TRS was higher in the StimOFF condition (TRS: 23) and slightly improved to a TRS of 17 when using 180 Hz stimulation. Conclusions: Here, we report the first case of a patient with SCA 27 successfully treated with VIM-DBS in terms of tremor attenuation. We observed that low-frequency stimulation at night led to a more sustained tremor response by stimulation which may be due to antidromic stimulation of cerebellar-thalamic fibre tracts in the subthalamic area.

Benefits from Repetitive Transcranial Magnetic Stimulation in Post-Stroke Rehabilitation.

Stroke is an acute neurovascular central nervous system (CNS) injury and one of the main causes of long-term disability and mortality. Post-stroke rehabilitation as part of recovery is focused on relearning lost skills and regaining independence as much as possible. Many novel strategies in neurorehabilitation have been introduced. This review focuses on current evidence of the effectiveness of repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation (NIBS), in post-stroke rehabilitation. Moreover, we present the effects of specific interventions, such as low-frequency or high-frequency rTMS therapy, on motor function, cognitive function, depression, and aphasia in post-stroke patients. Collected data suggest that high-frequency stimulation (5 Hz and beyond) produces an increase in cortical excitability, whereas low-frequency stimulation (≤1 Hz) decreases cortical excitability. Accumulated data suggest that rTMS is safe and can be used to modulate cortical excitability, which may improve overall performance. Side effects such as tingling sensation on the skin of the skull or headache are possible. Serious side effects such as epileptic seizures can be avoided by adhering to international safety guidelines. We reviewed clinical studies that present promising results in general recovery and stimulating neuroplasticity. This article is an overview of the current rTMS state of knowledge related to benefits in stroke, as well as its cellular and molecular mechanisms. In the stroke rehabilitation literature, there is a key methodological problem of creating double-blinding studies, which are very often impossible to conduct.

Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Hyperbaric Oxygen (HBO) on Awakening of Coma Patients with Traumatic Brain Injury.

Coma caused by craniocerebral injury is a common condition of neurosurgical acute injury. There is no specific method to promote awakening in a clinic. Early comprehensive treatment may be helpful to patients. The common methods are hyperbaric oxygen (HBO) and low-frequency repetitive transcranial magnetic stimulation (rTMS). However, the application effect and mechanism of rTMS combined with HBO on coma patients with traumatic brain injury need to be further studied. The brain stem auditory evoked potential (BAEP) is examined by the Kennedy coma recovery scale (CRS-R), the recovery of brain function and the state of consciousness are evaluated, and the therapeutic effect is evaluated by the Glasgow Coma Scale (GCS). Cerebrospinal fluid NE level, MCA blood flow velocity, and left brainstem and right brainstem auditory evoked potential are used to evaluate brain rehabilitation. RTMS combined with HBO could shorten the wake-up time, improve the wake-up rate, improve the GCS score and CRS-R score, shorten the brain wave latency time of the left and right brainstem, increase the NE level of cerebrospinal fluid, and decrease the blood flow velocity of MCA. RTMS combines with HBO can improve the nerve excitability of brain cells, reduce the disturbance of consciousness, promote the functional recovery of brain injury, and has a certain role in promoting the awakening of patients with traumatic brain injury coma.

Altered Spontaneous Brain Activity Patterns in Children With Strabismic Amblyopia After Low-Frequency Repetitive Transcranial Magnetic Stimulation: A Resting-State Functional Magnetic Resonance Imaging Study

ObjectivePrevious studies have demonstrated altered brain activity in strabismic amblyopia (SA). In this study, low-frequency repetitive transcranial magnetic stimulation (rTMS) was applied in children with strabismic amblyopia after they had undergone strabismus surgery. The effect of rTMS was investigated by measuring the changes of brain features using the amplitude of low-frequency fluctuation (ALFF).Materials and MethodsIn this study, 21 SA patients (12 males and 9 females) were recruited based on their age (7–13 years old), weight, and sex. They all had SA in their left eyes and they received rTMS treatment one month after strabismus surgery. Their vision before and after surgery were categorized as pre-rTMS (PRT) and post-rTMS (POT). All participants received rTMS treatment, underwent magnetic resonance imaging (MRI), and their data were analyzed using the repeated measures t-test. The team used correlation analysis to explore the relationship between logMAR visual acuity and ALFF.ResultsPre- versus post-rTMS values of ALFF were significantly different within individuals. In the POT group, ALFF values were significantly decreased in the Angular_R (AR), Parietal_Inf_L (PIL), and Cingulum_Mid_R (CMR) while ALFF values were significantly increased in the Fusiform_R (FR) and Frontal_Inf_Orb_L(FIL) compared to the PRT stage.ConclusionOur data showed that ALFF recorded from some brain regions was changed significantly after rTMS in strabismic amblyopes. The results may infer the pathological basis of SA and demonstrate that visual function may be improved using rTMS in strabismic amblyopic patients.

Low-frequency electrical stimulation promotes the recovery of gastrointestinal motility following gynecological laparoscopy (Review).

The rapid recovery of gastrointestinal transit is critical for clinical recovery following laparoscopic procedures, including gynecological laparoscopies (GLs). Rehabilitation interventions post-surgery may provide significant prevention against early post-operative gastrointestinal motility disorders and maid aid in the acceleration of post-operative recovery in patients undergoing GLs. Among others, low-frequency electrical stimulation (LFES) has been demonstrated to pronouncedly mitigate the symptoms caused by gastrointestinal motility disorders; thus, this has attracted increasing attention over the past decade. The present study aimed to present an overview of the efficacy and application of LFES in gastrointestinal motility recovery following GL procedures.

Clinical effects of continuous theta burst stimulation for generalized anxiety disorder and a mechanism involving α oscillations: a randomized controlled trial.

BackgroundContinuous theta burst stimulation (cTBS) is a much more rapid protocol than low-frequency repetitive transcranial magnetic stimulation (rTMS), but no clinical trial has yet investigated the efficacy and mechanisms of cTBS for the treatment of generalized anxiety disorder. The purpose of this study was to compare the clinical effects and α oscillations induced by cTBS versus 1 Hz rTMS as predictors of response, and to assess the underlying mechanisms of the therapeutic effects of cTBS in patients with generalized anxiety disorder.MethodsWe randomly allocated 120 patients with generalized anxiety disorder to receive cTBS (n = 41), 1 Hz rTMS (n = 40) or sham cTBS (n = 39) over the right dorsolateral prefrontal cortex; we also included healthy controls (n = 30) to compare neurophysiological data. We analyzed changes in Hamilton Anxiety Rating Scale scores and α oscillations (frequency and power) at baseline, post-treatment and 1-month follow-up.ResultsAfter 20 sessions of treatment, patients’ anxiety had improved and α power had increased in the cTBS and 1 Hz rTMS groups. However, at 1-month follow-up the cTBS group had significantly more responders and remitters, and higher α oscillations than the 1 Hz rTMS group (post hoc analysis: cTBS > rTMS > sham). At baseline, α frequency was inversely correlated with psychological symptom scores on the Hamilton Anxiety Rating Scale (r = −0.613, p < 0.001); post-treatment, this correlation was present only in the cTBS group (r = −0.685, p < 0.001).LimitationsElectroencephalography data were limited to the α band.ConclusionOur findings provide evidence for the clinical use of cTBS, a novel brain stimulation protocol. Its therapeutic effects may be the result of increasing α frequency, thereby improving the psychological symptoms of generalized anxiety disorder.

Fully Implantable Neural Stimulator with Variable Parameters

Neural implantable systems have promoted the development of neurosurgery research and clinical practice. However, traditional tethered neural implants use physical wires for power supply and signal transmission, which have many restrictions on implant targets. Therefore, untethered, wireless, and controllable neural stimulation has always been widely recognized as the engineering goal of neural implants. In this paper, magnetically coupled resonant wireless power transfer (MCR-WPT) technology is adopted to design and manufacture a wireless stimulator for the electrical stimulation experiment of nerve repair. In the process of device development, SCM technology, signal modulation, demodulation, wireless power supply, and integration/packaging are used. Through experimental tests, the stimulator can output single-phase pulse signals with a variable frequency of (1–20 Hz), a duty cycle of (1–50%), and voltage. The average power is approximately 25 mW. The minimum pulse width of the signal is 200 μs and the effective distance of transmission is 1–4 cm. The stimulator can perform low-frequency, safe and controllable wireless stimulation.

Synaptic plasticity in hippocampal CA1 neurons of mice lacking inositol-1,4,5-trisphosphate receptor-binding protein released with IP3 (IRBIT).

In hippocampal CA1 neurons of wild-type mice, a short tetanus (15 or 20 pulses at 100 Hz) or a standard tetanus (100 pulses at 100 Hz) to a naive input pathway induces long-term potentiation (LTP) of the responses. Low-frequency stimulation (LFS; 1000 pulses at 1 Hz) 60 min after the standard tetanus reverses LTP (depotentiation [DP]), while LFS applied 60 min prior to the standard tetanus suppresses LTP induction (LTP suppression). We investigated LTP, DP, and LTP suppression of both field excitatory postsynaptic potentials and population spikes in CA1 neurons of mice lacking the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-binding protein released with IP3 (IRBIT). The mean magnitudes of LTP induced by short and standard tetanus were not different in mutant and wild-type mice. In contrast, DP and LTP suppression were attenuated in mutant mice, whereby the mean magnitude of responses after LFS or tetanus were significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, IRBIT is involved in DP and LTP suppression, but is not essential for LTP. The attenuation of DP and LTP suppression in mice lacking IRBIT indicates that this protein, released during or after priming stimulations, determines the direction of LTP expression after the delivery of subsequent stimulations.

Low-frequency stimulation of a fiber tract in bilateral temporal lobe epilepsy

ObjectivePharmacoresistant bilateral mesial temporal lobe epilepsy often implies poor resective surgical candidacy. Low-frequency stimulation of a fiber tract connected to bilateral hippocampi, the fornicodorsocommissural tract, has been shown to be safe and efficacious in reducing seizures in a previous short-term study. Here, we report a single-blinded, within-subject control, long-term deep-brain stimulation trial of low-frequency stimulation of the fornicodorsocommissural tract in bilateral mesial temporal lobe epilepsy. Outcomes of interest included safety with respect to verbal memory scores and reduction of seizure frequency. MethodsOur enrollment goal was 16 adult subjects to be randomized to 2-Hz or 5-Hz low-frequency stimulation of the fornicodorsocommissural tract starting at 2 mA. The study design consisted of four two-month blocks of stimulation with a 50%-duty cycle, alternating with two-month blocks of no stimulation. ResultsWe terminated the study after enrollment of five subjects due to slow accrual. Fornicodorsocommissural tract stimulation elicited bilateral hippocampal evoked responses in all subjects. Three subjects underwent implantation of pulse generators and long-term low-frequency stimulation with mean monthly seizures of 3.14 ± 2.67 (median 3.0 [IQR 1–4.0]) during stimulation-off blocks, compared with 0.96 ± 1.23 (median 1.0 [IQR 0–1.0]) during stimulation-on blocks (p = 0.0005) during the blinded phase. Generalized Estimating Equations showed that low-frequency stimulation reduced monthly seizure-frequency by 0.71 per mA (p < 0.001). Verbal memory scores were stable with no psychiatric complications or other adverse events. SignificanceThe results demonstrate feasibility of stimulating both hippocampi using a single deep-brain stimulation electrode in the fornicodorsocommissural tract, efficacy of low-frequency stimulation in reducing seizures, and safety as regards verbal memory.

Effects of combining two techniques of non-invasive brain stimulation in subacute stroke patients: a pilot study

BackgroundStrokes have recently become a leading cause of disability among Thai people. Non-invasive brain stimulation (NIBS) seems to give promising results in stroke recovery when combined with standard rehabilitation programs.ObjectiveTo evaluate the combined effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) and cathodal transcranial direct current stimulation (tDCS) over the non-lesional primary motor cortex on upper limb motor recovery in patients with subacute stroke. No reports of a combination of these two techniques of NIBS were found in the relevant literature.MethodsThis pilot study was a double-blinded, randomized controlled trial of ten patients with subacute stroke admitted to the Rehabilitation Medicine Inpatient Unit, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University. They were randomized into two groups: five in an active and five in a sham intervention group. Fugl-Meyer’s upper extremity motor score (FMA-UE) and Wolf Motor Function Test (WMFT) were used to assess motor recovery at baseline, immediately, and 1 week after stimulation.ResultsA two-way repeated ANOVA (mixed design) showed a significant improvement in FMA-UE scores in the active intervention group both immediately and 1 week after stimulation in comparison to the baseline, [time, F (2, 16) = 27.44, p < 0.001, time x group interaction, F (2, 16) = 13.29, p < 0.001]. Despite no statistical significance, a trend toward higher WMFT scores was shown in the active intervention group.ConclusionsA single session of low-frequency rTMS and cathodal tDCS over the non-lesional primary motor cortex may enhance upper limb motor recovery in patients with subacute stroke.

LIU Zhi-shun's experience in treatment of infertility with decreasing ovarian reserve with electroacupuncture

To summarize LIU Zhi-shun's clinical experience in treatment of infertility with decreasing ovarian reserve (DOR) with electroacupuncture. LIU Zhi-shun believes that the location of infertility with DOR is the uterus, mainly involving the kidney, thoroughfare and conception vessels. He advocates to select acupoints by combining "disease-symptom-position" with prescription, and selects acupoint prescription of Bushen Tiaochong Zhuyun included Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25), Sanyinjiao (SP 6), Ciliao (BL 32) and Zhongliao (BL 33) for electroacupuncture treatment. The key points of operation are accurate positioning and deep acupuncture, focusing on regulating mind and getting qi, adopting electroacupuncture treatment and low frequency stimulation and treating slowly for long-term disease.

Impact of low-frequency rTMS on functional connectivity of the dentate nucleus subdomains in schizophrenia patients with auditory verbal hallucination

Despite low-frequency repetitive transcranial magnetic stimulation (rTMS) is effective in treating schizophrenia patients with auditory verbal hallucinations (AVH), the underlying neural mechanisms of the effect still need to be clarified. Using the cerebellar dentate nucleus (DN) subdomain (dorsal and versal DN) as seeds, the present study investigated resting state functional connectivity (FC) alternations of the seeds with the whole brain and their associations with clinical responses in schizophrenia patients with AVH receiving 1 Hz rTMS treatment. The results showed that the rTMS treatment improved the psychiatric symptoms (e.g., AVH and positive symptoms) and certain neurocognitive functions (e.g., visual learning and verbal learning) in the patients. In addition, the patients at baseline showed increased FC between the DN subdomains and temporal lobes (e.g., right superior temporal gyrus and right middle temporal gyrus) and decreased FC between the DN subdomains and the left superior frontal gyrus, right postcentral gyrus, left supramarginal gyrus and regional cerebellum (e.g., lobule 4–5) compared to controls. Furthermore, these abnormal DN subdomain connectivity patterns did not persist and decreased FC of DN subdomains with cerebellum lobule 4–5 were reversed in patients after rTMS treatment. Linear regression analysis showed that the FC difference values of DN subdomains with the temporal lobes, supramarginal gyrus and cerebellum 4–5 between the patients at baseline and posttreatment were associated with clinical improvements (e.g., AVH and verbal learning) after rTMS treatment. The results suggested that rTMS treatment may modulate the neural circuits of the DN subdomains and hint to underlying neural mechanisms for low-frequency rTMS treating schizophrenia with AVH.

The Effect of Lower Limb Neuromuscular Electrical Stimulation on Skeletal Muscle Signaling for Glucose Utilization and Systemic Inflammation After Acute Spinal Cord Injury

<h3>Research Objectives</h3> To quantify the effects of a novel combination neuromuscular electrical stimulation (Comb-NMES) training program on muscle signaling for glucose utilization and systemic inflammatory blood markers in individuals with acute spinal cord injury (SCI). <h3>Design</h3> Randomized controlled clinical trial. <h3>Setting</h3> In-patient rehabilitation setting. <h3>Participants</h3> 12 participants between 30.3 ±8.6, with an SCI between C6-L1, within 14 days of the SCI and with no history of diabetes, participated in the study. Muscle samples were collected from the Vastus Lateralis muscle within 14 days of SCI and before discharge from the Spain Rehabilitation hospital. <h3>Interventions</h3> The intervention group received Comb-NMES training program that combines dynamic contractions (resistance training) via high-frequency electrical stimulation with twitch contractions (aerobic training) via low-frequency electrical stimulation on the quadriceps muscle group on both legs. The control group received (sham treatment) passive dynamic exercise of the lower legs and transcutaneous electrical nerve stimulation (TENS). Interventions were given 3 times/week for 3-4 weeks. <h3>Main Outcome Measures</h3> Western blot analysis was performed to quantify signaling proteins (GLUT4, AMPKα, Hexokinase II, CaMKII, Akt, AS160, IRS-1, ACC, GS, and PI3 Kinase) for muscle glucose uptake. In addition, assays were performed to measure the serum proinflammatory and anti-inflammatory cytokines (IFN-γ, IL-10, IL-12p70, IL-1β, IL-6, IL-8, AND TNF-α). <h3>Results</h3> Protein expression for Akt, AMPKα, AS160, CaMKII, GLUT4, Hexokinase II, and PI3 Kinase and circulating levels of anti-inflammatory cytokine IL-10 and IFN-γ increased following Comb-NMES training program. <h3>Conclusions</h3> This preliminary data suggests that Comb-NMES training may increase the expression of proteins for glucose uptake and utilization in the paralyzed skeletal muscle. In addition, Comb-NMES training may increase circulating anti-inflammatory cytokines. This trial is ongoing, and results may change with a larger sample size. <h3>Author(s) Disclosures</h3> All authors listed in this abstract have no conflict of interest. this study is funded by NIH.

Repetitive transcranial magnetic stimulation for prophylactive treatment of chronic migraine: A randomised, single-blind, parallel-group, sham-controlled trial

Background: Pilot studies suggest that repetitive transcranial magnetic stimulation could be effective in migraine. We studied its efficacy for prophylaxis of chronic migraine. Methods: We undertook a randomised, single-blind, sham-controlled study in patients with chronic migraine. Subjects were randomly allocated to sham, high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) or low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). The primary outcome was the reduction of attacks at four weeks. In addition, reduction of severity of headache based on the Visual Analogue Scale score at two &amp; four weeks and a functional disability score at four weeks was recorded. Results: One hundred and eight patients were allocated to sham stimulation (n=36), HF-rTMS (n=36) and LF-rTMS (n=36) groups. The number of attacks per month decreased to 7.05+/-1.45 at four weeks post-rTMS in the HF-rTMS (p&lt;0.001) as compared to the LF-rTMS (10.61+/-1.69) and sham (10.83+/-3.37) groups. The VAS score in the HF-rTMS group was significantly lowered (p &lt; 0.001) from 8.61+/-1.15 at baseline to 6.63+/-0.96, and 7.19+/-0.98 at two and four weeks respectively. The duration of headache in hours over 4 weeks reduced from 32.4+/-14.9 to 11.6+/-6.14 in the HF-rTMS group (p&lt;0.001), but did not change significantly in the LF-rTMS (30.4+/-11.9 to 27.8+/-14, p&gt;0.05) and sham (26.8+/-11.06 to 37+/-15, p&gt;0.05) in sham groups. There was no significant difference in functional disability between all the study groups at four weeks. Conclusion: High-frequency, but not low-frequency, repetitive transcranial magnetic stimulation may be useful in management of chronic migraine.

Experience of Rhythmic Peripheral Magnetic Stimulation Application in the Treatment of Pareses of Various Etiologies at the Foot Level and the Objectiveness of Assessing the Dynamics of Motor Disorders. Literature Review

The aim of this work is to study the current issue state of using rhythmic peripheral magnetic stimulation (rPMS) in the rehabilitation of patients with paresis of the lower extremities with lower lumbar radiculopathy. The article presents information on the use of rPMS in the rehabilitation of patients with motor impairments in various diseases. The world experience of the effectiveness and reliability of the technique application in patients with various motor disorders has been analyzed. It is clarified that this direction in the domestic and foreign literature is represented by few works, and the rehabilitation of patients with paresis of the foot after discectomy at the lower lumbar level is insufficiently expanded on a topic. Conclusion. Our literature analysis shows a good clinical effect of using low-frequency stimulation in the treatment of motor disorders, which turned out to be identical to that obtained by a number of authors who used low-frequency rTMS in similar studies. The issue of using the rPMS method in the rehabilitation of patients with paresis of the lower extremities remains relevant and promising.

Target-specific control of olfactory bulb periglomerular cells by GABAergic and cholinergic basal forebrain inputs.

The olfactory bulb (OB), the first relay for odor processing in the brain, receives dense GABAergic and cholinergic long-range projections from basal forebrain (BF) nuclei that provide information about the internal state and behavioral context of the animal. However, the targets, impact, and dynamic of these afferents are still unclear. How BF synaptic inputs modulate activity in diverse subtypes of periglomerular (PG) interneurons using optogenetic stimulation and loose cell-attached or whole-cell patch-clamp recording in OB slices from adult mice were studied in this article. GABAergic BF inputs potently blocked PG cells firing except in a minority of calretinin-expressing cells in which GABA release elicited spiking. Parallel cholinergic projections excited a previously overlooked PG cell subtype via synaptic activation of M1 muscarinic receptors. Low-frequency stimulation of the cholinergic axons drove persistent firing in these PG cells, thereby increasing tonic inhibition in principal neurons. Taken together, these findings suggest that modality-specific BF inputs can orchestrate synaptic inhibition in OB glomeruli using multiple, potentially independent, inhibitory or excitatory target-specific pathways.

Frequency dependency of therapeutic efficacy in dorsal root ganglion stimulation for neuropathic pain

BackgroundThe influence of the stimulation frequency on the outcomes of dorsal root ganglion stimulation (DRG-S) to treat pain is not well understood. It is assumed that specific neural components dedicated to different tasks in the DRG can be preferably influenced at specific frequencies. The identification of frequencies designed for the type of pain and the ratio of neuropathic versus nociceptive pain might improve overall pain control and open new indications in DRG-S.MethodWe report on a randomized double-blind clinical trial with a crossover design. Patients with a permanent DRG-S system underwent phases of stimulation with 20 Hz, 40 Hz, 60 Hz, 80 Hz, and sham in a randomized order. Each phase lasted for 4 days and was followed by a 2-day washout period. Pain intensity and quality of life were assessed with visual analog scale (VAS), McGill Pain Questionnaire (MPQ), EQ-5D, and Beck Depression Inventory (BDI). Analgesics intake was assessed.ResultsOverall 19 patients were included in the study. CRPS was the most frequent pain etiology (7). Five patients had a PainDetect score of 12 or lower at baseline. The mean VAS before the system was implanted was 8.6 and 3.9 at the baseline. Pain intensity was reduced to 3.7 by the stimulation with 20 Hz but increased with higher frequencies reaching 5.8 at 80 Hz. A significant difference among the groups was shown over all variables examined (VAS, MPQ, EQ-5D, BDI). The best results were seen at 20 Hz for all variables, including the smallest increase in pain medication consumption.ConclusionsThe choice of the stimulation frequency shows a clear influence on pain reduction and quality of life. Lower stimulation frequencies seem to be most effective in neuropathic pain. Further studies are required to determine whether specific frequencies should be preferred based on the condition treated.

Electrophysiological and Imaging Analysis of GFP-Tagged Protein Kinase C γ Translocation in Cerebellar Purkinje Cells.

The cerebellum contains the highest density of protein kinase C (PKC) in the central nervous system. PKCγ, the major isotype accounting for over half of the PKCs in the cerebellum, is expressed exclusively in Purkinje cells (PCs). Inactivated PKCγ, which is localized in the cytoplasm of PC dendrites and soma, begins to translocate to the cell membrane upon activation. However, the physiological conditions that induce PKCγ translocation in PC remain largely unknown. Here, we virally expressed PKCγ-GFP in PCs and examined the conditions that induced its translocation to PC dendrites by whole-cell patch clamp analysis combined with confocal GFP fluorescence imaging. A single or repetitive (150 pulses at 5Hz for 30s) electrical stimulation to a climbing fiber (CF), which produced a complex spike(s) in PC, failed to induce translocation of PKCγ-GFP to the dendritic shaft of PCs. Direct current injection (+ 2 nA for 3s) to PC also did not induce the translocation, although PCs generated simple spikes continuously at high rates. In contrast, high-frequency parallel fiber (PF) stimulation (50 pulses at 50Hz for 1s), which triggered action potentials followed by sustained depolarization (known as mGluR1-mediated slow depolarization), caused translocation of cytoplasmic PKCγ-GFP to the membrane. Low-frequency PF stimulation (150 pulses at 5Hz for 30s) induced continuous simple spike firing but did not induce translocation. These results suggest that CF-triggered depolarization, which causes Ca2+ influx through voltage-gated Ca2+ channels throughout PC dendrites and somas, is insufficient to induce the translocation of PKCγ, instead requiring high-frequency PF stimulation that activates mGluR1.

Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses.

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases, characterized by progressive cerebral atrophy due to lysosomal storage disorder. Common clinical features include epileptic seizures, progressive cognitive and motor decline, and visual failure, which occur over different time courses according to subtypes. During the latest years, many advances have been done in the field of targeted treatments, and in the next future, gene therapies and enzyme replacement treatments may be available for several NCL variants. Considering that there is rapid disease progression in NCLs, an early diagnosis is crucial, and neurophysiological features might have a key role for this purpose. Across the different subtypes of NCLs, electroencephalogram (EEG) is characterized by a progressive deterioration of cerebral activity with slowing of background activity and disappearance of spindles during sleep. Some types of heterogeneous abnormalities, diffuse or focal, prevalent over temporal and occipital regions, are described in many NCL variants. Photoparoxysmal response to low-frequency intermittent photic stimulation (IPS) is a typical EEG finding, mostly described in CLN2, CLN5, and CLN6 diseases. Visual evoked potentials (VEPs) allow to monitor the visual functions, and the lack of response at electroretinogram (ERG) reflects retinal neurodegeneration. Taken together, EEG, VEPs, and ERG may represent essential tools toward an early diagnosis of NCLs.

α7 nicotinic acetylcholine receptor modulation of accumbal dopamine release covaries with novelty seeking.

Heightened novelty-seeking phenotypes are associated with a range of behavioural traits including susceptibility to drug use. These relationships are recapitulated in preclinical models, where rats that exhibit increased exploratory activity in novel environments (high responders-HR) acquire self-administration of psychostimulants more rapidly compared to rats that display low novelty exploration (low responders-LR). Dopamine release dynamics in the nucleus accumbens (NAc) covaries with response to novelty, and differences in dopaminergic signalling are thought to be a major underlying driver of the link between novelty seeking and drug use vulnerability. Accumbal dopamine release is controlled by local microcircuits including modulation through glutamatergic and nicotinic acetylcholine receptor (nAChR) systems, but whether these mechanisms contribute to disparate dopamine signalling across novelty phenotypes is unclear. Here, we used ex vivo voltammetry in the NAc of rats to determine if α7 nAChRs contribute to differential dopamine dynamics associated with individual differences in novelty exploration. We found that blockade of α7 nAChRs attenuates tonic dopamine release evoked by low-frequency stimulations across phenotypes but that phasic release is decreased in LRs while HRs are unaffected. These stimulation frequency- and phenotype-dependent effects result in a decreased dynamic range of release exclusively in LRs. Furthermore, we found that differential α7 modulation of dopamine release in LRs is dependent on AMPA but not NMDA receptors. These results help to form an understanding of the local NAc microcircuitry and provide a potential mechanism for covariance of dopamine dynamics and sensitivity to the reinforcing effects of drugs of abuse.