Low-frequency Stimulation Research Articles

LTD‐inducing low frequency stimulation enhances p‐Tau181 and p‐Tau217 in an age‐dependent manner in live rats

AbstractBackgroundThe progressive cognitive decline in Alzheimer’s disease (AD) patients correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age‐associated. Although elevation of phosphorylated tau (p‐Tau) on residues Thr181 (p‐Tau181), Thr217 (p‐Tau217), and Thr231 (p‐Tau231) in cerebrospinal fluid or blood are recently proposed to be particularly sensitive markers of early Alzheimer’s disease (AD), the generation of p‐Tau during brain activity is poorly understood. A major form of synaptic plasticity, long‐term depression (LTD), has recently been linked to the enhancement of tau phosphorylation. It is still unknown whether the expression levels of p‐Tau181, p‐Tau217, and p‐Tau231 can be enhanced by physiological LTD induction.MethodYoung adult (2‐3‐months) and aged (17‐18‐months) male Sprague Dawley rats were used in all experiments. Prior to the surgery, animals were anesthetized with urethane (1.5‐1.6 g/kg, i.p.). Field excitatory postsynaptic potentials (EPSPs) were recorded from the stratum radiatum in the CA1 area of left or right hippocampus in response to stimulation of the Schaffer collateral‐commissural pathway. LTD was induced using 1 Hz low frequency stimulation (LFS) consisting of 900 pulses (0.2 ms duration). The rats were sacrificed 30 min post‐LFS. The expression levels of p‐Tau181, p‐Tau217, p‐Tau231, p‐Tau202/205, p‐Tau396, and total tau were analyzed using western blotting and immunofluorescent staining.ResultHere we show that LFS, used to induce LTD, enhances p‐Tau181 and p‐Tau217 in an age‐dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 is less sensitive to LFS. Further, blocking either NMDARs or mGluR5 strongly inhibits the elevation of both p‐Tau181 and p‐Tau217. Finally, targeting ageing with a small molecule cognitive enhancer ISRIB (trans‐isomer) prevents the increase of both p‐Tau181 and p‐Tau217 by LFS in aged rats.ConclusionOur data provide an in vivo means to uncover brain plasticity‐related cellular and molecular processes of tau phosphorylation in health and ageing conditions.

ID: 210321 Effect of Low-Frequency Dorsal Root Ganglion Stimulation in the Treatment of Neuropathic and Nociceptive Pain

The role of stimulation parameters in dorsal root ganglion stimulation (DRG-S), especially of stimulation frequency, is not well understood. Previous studies documented higher effectiveness for frequencies as low as 20 Hz, but there is evidence that even lower values could lead to better outcomes. In this study, we investigate the influence of low-frequency DRG-S.

ID: 220244 A Single-Center Review of 10 kHz Spinal Cord Stimulator Treatment Outcomes for Chronic Pain

Chronic pain is a prevalent worldwide condition, leading to diminished quality of life and workforce productivity (1). First-line therapies from conservative medical management to surgery have demonstrated varying degrees of efficacy, though sustained long-term pain management remains a challenge (2). Low-frequency spinal cord stimulation (LF-SCS) has been used in a subset of patients as a cost-effective and minimally invasive therapy to achieve pain control and improved quality of life (3). However, its limitations include diminished long-term relief, uncomfortable paresthesia, and incomplete pain control (4). The pivotal SENZA-RCT in 2015 demonstrated the efficacy of 10 kHz (high-frequency) spinal cord stimulation (HF-SCS) as a superior alternative to LF-SCS (5). The study, although promising, was industry-sponsored and potentially vulnerable to bias including withholding of negative data or exaggeration of beneficial effects. The goal of this single-center retrospective review was to compare outcomes of real-world/pragmatic HF-SCS pain outcomes to previously published studies without the potential bias of industry funding.

Long-term depression induction and maintenance across regions of the apical branch of CA1 dendrites.

Well known as the center for learning and memory, hippocampus is the crucial brain region to study synaptic plasticity in the context of cellular fundamental mechanisms such as long-term depression (LTD) and long-term potentiation (LTP). However, despite years of extensive research, the key to our LTD queries and their induction mechanisms has not been fully understood. Previously, we reported the induction of late-LTD (L-LTD) in the distally located synapses of apical branch of hippocampal CA1 dendrites using strong low-frequency stimulation (SLFS). In contrast synapses at the proximal site could not express L-LTD. Thus, in the present study, we wanted to investigate whether or not synapses of apical dendritic branch at the proximal location could induce and maintain LTD and its related properties in in vitro rat hippocampal slices. Results indicated that the SLFS in the distal and proximal region triggered the plasticity related proteins (PRP) synthesis in both regions, as evident by the induction and maintenance of L-LTD in the distal region by virtue of synaptic and cross-tagging. In addition, the application of emetine at the time of proximal input stimulation prevented the transition of early-LTD (E-LTD) into L-LTD at the distal region, proving PRP synthesis at the proximal site. Further, it was observed that weak low-frequency stimulation (WLFS) could induce E-LTD in the proximal region along with LTD-specific tag-setting at the synapses. In conclusion, the current study suggests unique findings that the synaptic and cross-tagging mediate L-LTD expression is maintained in the proximal location of hippocampus apical CA1 dendrites.

0508 Adherence with Transoral Neuromuscular Electrical Stimulation Therapy in Veterans with Mild OSA

Abstract Introduction Mild obstructive sleep apnea (OSA) is increasingly common in the VA. The first-line therapies are medical devices worn each night while asleep to control or manage OSA. These devices are burdensome for our patients with mild OSA. Stronger oral musculature can help reduce mild OSA. A new transoral Neuromuscular Electrical Stimulation (NMES) device was recently approved by the US FDA called eXciteOSA (Signifier Medical Technologies, Needham, MA). The eXciteOSA device provides gentle, low-frequency electrical stimulation intraorally to the tongue muscle and is efficacious for mild OSA. Methods A retrospective review of the data of the 71 patients prescribed the eXciteOSA device at the VA San Diego was analyzed. The device is prescribed for use over two phases: (1) one 20-minute session per day over 42 consecutive days and then (2) one 20-minute session on two days out of each week. Respiratory therapists performed 1-2 phone call visits to assess symptoms and address device concerns. Results 68 of the 71 patients used the device for at least one 20-minute session over the first 42 days. Three patients (4.2%) did not use the device. Adherence was 60% for all 71 patients and 63% for the 68 patients who used it at least once. This means that, on average, our Veteran patients completed one 20-minute session on 25 of the first 42 days. Conclusion Recent non-Veteran data showed an adherence rate of ~80% (percentage of days with one completed 20-minute session over the first 42 days). Our analysis found an adherence rate of ~60%, suggesting significant room for improvement in eXciteOSA device use in Veterans. Future adherence studies should look at methods to improve device use over the first 42 days. In addition, more research may be needed to understand better what amount of use is efficacious on an individual basis. Some patients may obtain an adequate response with fewer sessions, while others may need more. It is unknown which endotypes of OSA most benefit from NMES, but further research is ongoing. Support (if any) VA RR&D D2651-R and the Sleep Medicine Section of the VA San Diego Healthcare System supported this project.

Mechanosensitive stem cell fate choice is instructed by dynamic fluctuations in activation of Rho GTPases

During the intricate process by which cells give rise to tissues, embryonic and adult stem cells are exposed to diverse mechanical signals from the extracellular matrix (ECM) that influence their fate. Cells can sense these cues in part through dynamic generation of protrusions, modulated and controlled by cyclic activation of Rho GTPases. However, it remains unclear how extracellular mechanical signals regulate Rho GTPase activation dynamics and how such rapid, transient activation dynamics are integrated to yield long-term, irreversible cell fate decisions. Here, we report that ECM stiffness cues alter not only the magnitude but also the temporal frequency of RhoA and Cdc42 activation in adult neural stem cells (NSCs). Using optogenetics to control the frequency of RhoA and Cdc42 activation, we further demonstrate that these dynamics are functionally significant, where high- vs. low-frequency activation of RhoA and Cdc42 drives astrocytic vs. neuronal differentiation, respectively. In addition, high-frequency Rho GTPase activation induces sustained phosphorylation of the TGFβ pathway effector SMAD1, which in turn drives the astrocytic differentiation. By contrast, under low-frequency Rho GTPase stimulation, cells fail to accumulate SMAD1 phosphorylation and instead undergo neurogenesis. Our findings reveal the temporal patterning of Rho GTPase signaling and the resulting accumulation of an SMAD1 signal as a critical mechanism through which ECM stiffness cues regulate NSC fate.

Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice.

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a 'dying back' type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca2+-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca2+]in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca2+ transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca2+ were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo-endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca2+ kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization.

The Anterior Cingulate Cortex is Critical for Acute Stress-induced Hypersensitivity in Mice

Stress can be categorized according to physical, psychological and social factors. Exposure to stress produces stress-induced hypersensitivity and forms negative emotions such as anxiety and depression. For example, acute physical stress induced by the elevated open platform (EOP) causes prolonged mechanical hypersensitivity. The anterior cingulate cortex (ACC) is a cortical region involved in pain and negative emotions. Recently, we showed that mice exposed to the EOP changed spontaneous excitatory, but not inhibitory transmission in layer II/III pyramidal neurons of the ACC. However, it is still unclear whether the ACC is involved in the EOP induced mechanical hypersensitivity, and how the EOP alters evoked synaptic transmission on excitatory and inhibitory synaptic transmission in the ACC. In this study, we injected ibotenic acid into the ACC to examine if it was involved in stress-induced mechanical hypersensitivity induced by EOP exposure. Next, by using whole-cell patch-clamp recording from brain slice preparation, we analyzed action potentials and evoked synaptic transmission from layer II/III pyramidal neurons within the ACC. Lesion of the ACC completely blocked the stress-induced mechanical hypersensitivity induced by EOP exposure. Mechanistically, EOP exposure mainly altered evoked excitatory postsynaptic currents such as input–output and paired pulse ratio. Intriguingly, the mice exposed in the EOP also produced low-frequency stimulation induced short-term depression on excitatory synapses in the ACC. These results suggest that the ACC plays a critical role in the modulation of stress-induced mechanical hypersensitivity, possibly through synaptic plasticity on excitatory transmission.

Effect of scalp acupuncture combined with low frequency repetitive transcranial magnetic stimulation on brain function of pediatric patients with spastic cerebral palsy

ObjectiveTo observe the changes of Electroencephalogram (EEG) spectrum in children with spastic cerebral palsy before and after treatment, and to analyze the effects of scalp acupuncture combined with low-frequency repetitive transcranial magnetic stimulation (rTMS) therapy on brain function. MethodsFrom January 2021 to December 2022, 90 children aged 2–6 with spastic cerebral palsy were treated at our hospital. The patients were divided into treatment and control groups. The treatment group (combined group, n = 30) received scalp acupuncture combined with low-frequency rTMS treatment. The control group received only scalp acupuncture treatment (n = 30) or rTMS treatment (n = 30). The Gross Motor Function Measure (GMFM), the modified Ashworth spasticity scale, and the Gesell scale were used to assess the motor and developmental functions of pediatric patients with spastic cerebral palsy in each group. ResultsThe patients in the three groups showed different degrees of improvement in EEG after treatment, mainly in wave amplitude reduction, background rhythm slowdown, background rhythm asymmetry improvement and spike and multi-spike/slow wave distribution reduction. The improvement in the scalp-acupuncture combined with low-frequency rTMS group was more significant than that in the other two groups. The GMFCS classification, modified Ashworth score, D and E areas of GMFM, and adaptability, gross motor, and language in Gesell Developmental Diagnostic Scale (GDDS) improved in all three groups after treatment (P < 0.05). In the combined group, the improvement in the modified Ashworth score, the E area of GMFM, and the adaptation, gross motor, and language in the GDDS was more significant than that in the other two groups (P < 0.05). ConclusionBy combining scalp acupuncture with low-frequency rTMS to treat children with spastic cerebral palsy, the brain function is improved by bringing the EEG spectrum towards the normal range, thus improving the mental and developmental functions of the child.

Low- and high-frequency spinal cord stimulation and arterial blood pressure in patients with chronic pain and hypertension: a retrospective study.

Evidence suggests that traditional low-frequency spinal cord stimulation (LF-SCS) reduces arterial blood pressure (BP) in patients with chronic pain and hypertension independent of improved pain symptoms. However, it remains unclear whether high-frequency spinal cord stimulation (HF-SCS) also lowers BP in chronic pain patients with hypertension. Therefore, in a retrospective study design, we tested the hypothesis that clinic BP would be significantly reduced following implantation of HF-SCS in patients with chronic pain and hypertension. Clinic BP within 3months before and after surgical implantation of either a LF-SCS or HF-SCS device between 2010 and 2020 were collected from electronic medical records at The University of Kansas Health System (TUKHS). A total of 132 patients had available records of clinic BP (64 ± 13years of age). Patients with hypertension (n = 32) demonstrated a significantly greater reduction in systolic BP (-8 ± 12 versus 2 ± 9mmHg, P < 0.001) following implantation compared with normotensive patients (n = 100). Importantly, the change in BP was inversely related to baseline BP independent of age and sex following implantation of HF-SCS (n = 70, R = -0.50, P < 0.001) or LF-SCS (n = 62, R = -0.42, P = 0.001). Higher pain scores before implantation were not associated with reduction in systolic BP (R = 0.10, P = 0.43) or diastolic BP (R = -0.08, P = 0.53) (n = 69) after implantation. These findings confirm previous studies showing reduced BP following implantation of LF-SCS in patients with chronic pain and hypertension and provide novel data regarding reduced BP following implantation of newer generation HF-SCS devices.

Noninvasive vagus nerve stimulation for migraine: a systematic review and meta-analysis of randomized controlled trials.

Medication is commonly used to treat migraine. However, patients may experience adverse events or fail to respond to medication. In recent years, neuromodulation techniques have emerged as potential non-pharmacological therapy for migraine. This article focuses on a systematic review and meta-analysis of randomized controlled trials of non-invasive vagus nerve stimulation (n-VNS) for migraine to determine the efficacy, safety and tolerability of n-VNS. We searched PUBMED, EMBASE, and Cochrane Center Register of Controlled Trials databases up to July 15, 2022. Primary outcomes were monthly reduced migraine/headache days, and pain-free rates within 2 h. Secondary outcomes were ≥ 50% responder rate, headache intensity, monthly acute medication reduction days, and adverse events. Meta-analysis shows that non-invasive cervical vagus nerve stimulation (n-cVNS) significantly impacted ≥50% responder rate (OR, 1.64; 95% CI, 1.1 to 2.47; p = 0.02), but had no significant effect on reducing migraine days (MD, -0.46; 95% CI, -1.21 to 0.29; p = 0.23) and headache days (MD, -0.68; 95% CI, -1.52 to 0.16; p = 0.11). In contrast, low-frequency non-invasive auricular vagus nerve stimulation (n-aVNS) was found to significantly reduce the number of migraine days (MD, -1.8; 95% CI, -3.34 to -0.26; p = 0.02) and headache intensity (SMD, -0.7; 95% CI, -1.23 to -0.17; p = 0.009), but not the number of acute medication days per month (MD, -1.1; 95% CI, -3.84 to 1.64; p = 0.43). In addition, n-cVNS was found safe and well-tolerated in most patients. These findings show that n-VNS is a promising method for migraine management.

Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).

Stimulation-induced respiratory enhancement in corticothalamic regions.

We aimed to identify corticothalamic areas and electrical stimulation paradigms that optimally enhance breathing. Twenty-nine patients with medically intractable epilepsy were prospectively recruited in an epilepsy monitoring unit while undergoing stereoelectroencephalographic evaluation. Direct electrical stimulation in cortical and thalamic regions was carried out using low (<1 Hz) and high (≥10 Hz) frequencies, and low (<5 mA) and high (≥5 mA) current intensities, with pulse width of .1 ms. Electrocardiography, arterial oxygen saturation (SpO2 ), end-tidal carbon dioxide (ETCO2 ), oronasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. Airflow signal was used to estimate breathing rate, tidal volume, and minute ventilation (MV) changes during stimulation, compared to baseline. Electrical stimulation increased MV in the amygdala, anterior cingulate, anterior insula, temporal pole, and thalamus, with an average increase in MV of 20.8% ± 28.9% (range = 0.2%-165.6%) in 19 patients. MV changes were associated with SpO2 and ETCO2 changes (p < .001). Effects on respiration were parameter and site dependent. Within amygdala, low-frequency stimulation of the medial region produced 78.49% greater MV change (p < .001) compared to high-frequency stimulation. Longer stimulation produced greater MV changes (an increase of 4.47% in MV for every additional 10 s, p = .04). Stimulation of amygdala, anterior cingulate gyrus, anterior insula, temporal pole, and thalamus, using certain stimulation paradigms, enhances respiration. Among tested paradigms, low-frequency, low-intensity, long-duration stimulation of the medial amygdala is the most effective breathing enhancement stimulation strategy. Such approaches may pave the way for the future development of neuromodulatory techniques that aid rescue from seizure-related apnea, potentially as a targeted sudden unexpected death in epilepsy prevention method.

Efficacy of different strategies of responsive neurostimulation on seizure control and their association with acute neurophysiological effects in rats

Responsive neurostimulation (RNS) has shown promising but limited efficacy in the treatment of drug-resistant epilepsy. The clinical utility of RNS is hindered by the incomplete understanding of the mechanism behind its therapeutic effects. Thus, assessing the acute effects of responsive stimulation (AERS) based on intracranial EEG recordings in the temporal lobe epilepsy rat model may provide a better understanding of the potential therapeutic mechanisms underlying the antiepileptic effect of RNS. Furthermore, clarifying the correlation between AERS and seizure severity may help guide the optimization of RNS parameter settings. In this study, RNS with high (130 Hz) and low frequencies (5 Hz) was applied to the subiculum (SUB) and CA1.To quantify the changes induced by RNS, we calculated the AERS during synchronization by Granger causality and analyzed the band power ratio in the classic power band after different stimulations were delivered in the interictal and seizure onset periods, respectively. This demonstrates that only targets combined with an appropriate stimulation frequency could be efficient for seizure control. High-frequency stimulation of CA1 significantly shortened the ongoing seizure duration, which may be causally related to increased synchronization after stimulation. Both high-frequency stimulation of the CA1 and low-frequency stimulation delivered to the SUB reduced seizure frequency, and the reduced seizure risk may correlate with the change in power ratio near the theta band. It indicated that different stimulations may control seizures in diverse manners, perhaps with disparate mechanisms. More focus should be placed on understanding the correlation between seizure severity and synchronization and rhythm around theta bands to simplify the process of parameter optimization.

Low-frequency Electrical Stimulation of the Hippocampus Plays a Role in the Treatment of Pharmacoresistant Epilepsy by Blocking the PKA-CREB Pathway.

The objective of this study is to study the mechanism of Low frequency electrical stimulation (LFS) in the treatment of drug-resistant epilepsy by regulating the protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling pathway upstream of gamma aminobutyric acid A (GABAA) receptor. Primary hippocampal neurons were extracted and cultured from fetal rat brains and randomly divided into the normal control group, PKA-CREB agonist group, and PKA-CREB inhibitor group. Drug-resistant epileptic rats were established and randomly divided into the pharmacoresistant group, LFS group, PKA-CREB agonist combined with hippocampal LFS group, and PKA-CREB inhibitor combined with hippocampal LFS group. The normal rats were in the normal control group and drug-sensitive rats were in the pharmacosensitive group. The seizure frequency of epileptic rats was determined using video surveillance. The expression of PKA, CREB, p-CREB, and GABAA receptor subunits α1 and β2 of each group were detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting assays. The in vitro expression levels of PKA, CREB, and p-CREB in the agonist group were significantly higher than those in the normal control group (NRC group), while the expression levels of GABAA receptor subunits α1 and β2 were significantly lower than those in the NRC group. The expression levels of PKA, CREB, and p-CREB in the inhibitor group were significantly lower, while the expression levels of GABAA receptor subunits α1 and β2 were significantly higher than those in the NRC group. The in vivo seizure frequency was significantly lower in the LFS group than in the pharmacoresistant group (PRE group). Compared to the LFS group, the seizure frequency and the expression levels of PKA, CREB, and p-CREB in the rat hippocampus were significantly higher, and the expression levels of GABAA receptor subunits α1 and β2 were significantly lower in the agonist group. The results in the inhibitor group were exactly the opposite of those in the agonist group. The PKA-CREB signaling pathway is involved in the regulation of GABAA receptor subunits α1 and β2. In addition, LFS plays an important role in increasing GABAA receptor expression by regulating the PKA-CREB signaling pathway.

Treatment of Medication-Resistant Neuropathic Pain in a Tetraplegic Patient Using Repetitive Transcranial Magnetic Stimulation (rTMS): A case report (P9-6.009)

<h3>Objective:</h3> N/A <h3>Background:</h3> Transcranial magnetic stimulation (TMS) is a non-invasive method of neuromodulation currently FDA-approved for the treatment of depression, but has also shown promising results in treating neuropathic pain. Given the risks of invasive neuromodulation and the dangers of long-term opioid use, especially in the face of an opioid crisis, it is imperative to find an effective treatment with minimal side effects. <h3>Design/Methods:</h3> The patient is a 74-year old tetraplegic Caucasian man who suffers from severe medication-resistant neuropathic pain following a spinal cord injury. TMS treatment was initiated, using a two-part protocol consisting of high-frequency (10 Hz) stimulation of the left dorsolateral prefrontal cortex (DLPFC) followed by low-frequency (5 Hz) stimulation of the primary motor (M1) cortex. Patient received daily treatment for the first week and decreased in frequency as treatment continued. Pain was measured using the Visual Analog Scale and tracked over 13 weeks (currently ongoing). <h3>Results:</h3> Patient’s pain level before beginning treatment was 6.35/10. Within the first week of treatment, his baseline pain level was reduced to 4.19/10. The lowest pain immediately following treatment was 1.9/10, a 70.1% decrease in pain scores. During the initial week of treatments, the patient reported that pain relief lasted for a few hours immediately following treatment. As treatment continued, he reported experiencing progressively longer relief, and also decreased his dosage of opioids due to the pain relief from the rTMS treatment. <h3>Conclusions:</h3> The pain protocol reduced medication-resistant neuropathic pain in our patient, as measured by the Visual Analog Scale as well as a decrease in opioid usage. Analgesic effects were additive with continual treatment. TMS treatment is non-invasive and could be administered without moving the patient from his wheelchair. The significant, lasting decrease in pain reported by the patient supports the need for further clinical studies of combined M1-rTMS and DLPFC-rTMS treatment for neuropathic pain. <b>Disclosure:</b> Miss Li has nothing to disclose. Dr. Kuluva has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Piedmont Neuroscience Center. Ms. Paras has nothing to disclose. Mr. Mohammad has nothing to disclose.

Punding in Parkinson's Disease: An Update.

Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, non-goal oriented, repetitive activity affecting individuals with Parkinson's disease (PD) on dopamine replacement therapy (DRT). In 2010, we published the first review focused on the pathophysiology of punding. This study aims to systematically review the literature of the past decade on punding in PD, particularly focusing on the clinical features, underlying pathophysiological mechanisms, and treatment. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase, and APA PsycInfo for articles published between July 1, 2010 and March 19, 2022. The search strategy included: (punding) AND (parkinson*). Of 256 studies identified, 29 were eligible for inclusion with 19 original research articles and 10 case reports. This review confirmed that predictors of punding in PD are higher doses of DRT, younger age, male sex, and increasing disease severity. We also found an association between punding and psychiatric and/or cognitive symptoms. Neuroimaging studies have showed that punding in PD is associated with a disconnection between midbrain, limbic and white matter tracts projecting to the frontal cortices and a breakdown of the connectivity among the crucial nodes of the reward circuit. Low-frequency repetitive transcranial magnetic stimulation on the dorsolateral prefrontal cortex has been shown to produce a transient beneficial effect in PD patients with punding. In conclusion, although the clinical features of punding have been established, in the past 12 years, we gained a better understanding of the pathophysiological mechanisms of punding, mainly thanks to magnetic resonance imaging techniques.

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice.

In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca2+ transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.

Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode

Learning, memory, and cognition are thought to require synaptic plasticity, specifically including hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high-frequency stimulation versus low-frequency, but stimulating β-adrenergic receptors (βARs) enables LTP induction also by low-frequency stimulation (1Hz) or theta frequencies (∼5Hz) that do not cause plasticity by themselves. In contrast to high-frequency stimulation-LTP, such βAR-LTP requires Ca2+-flux through L-type voltage-gated Ca2+-channels, not N-methyl-D-aspartate-type glutamate receptors. Surprisingly, we found that βAR-LTP still required a nonionotropic scaffolding function of the N-methyl-D-aspartate-type glutamate receptor: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to its GluN2B subunit that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, β-adrenergic stimulation with isoproterenol (Iso) transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, Iso enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased surface expression of GluA1 fused with super-ecliptic pHluorein. Like for βAR-LTP in hippocampal slices, the Iso effects on CaMKII movement and surface expression of GluA1 fused with super-ecliptic pHluorein involved L-type Ca2+-channels and specifically required β2-ARs. Taken together, these results indicate that Iso transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode.

Right arcuate fasciculus as outcome predictor after low-frequency repetitive transcranial magnetic stimulation in nonfluent aphasic stroke.

A reliable neuroimaging biomarker to predict language improvement after neuromodulation in post-stroke aphasia is lacking. It is hypothesized that aphasic patients with stroke injuries in the left primary language circuits but with sufficient right arcuate fasciculus (AF) integrity might respond to low-frequency repetitive transcranial magnetic stimulation (LF-rTMS), leading to language improvement. This study aimed to assess the microstructural indices of the right AF before LF-rTMS treatment and further correlate with language improvement after the treatment. Thirty-three patients with at least 3 months after stroke in the left hemisphere and nonfluent aphasia were recruited in this randomized double-blind study. All patients received real 1-Hz LF-rTMS (n = 16) or sham stimulation (n = 17) at the right pars triangularis for 10 consecutive weekdays. Fractional anisotropy, axial diffusivity, radial diffusivity and apparent diffusion coefficient of the right AF were extracted using diffusion tensor imaging before the rTMS treatment and correlated with the measured functional improvement by the Concise Chinese Aphasia Test. The Concise Chinese Aphasia Test change scores revealed a stronger language improvement in auditory/reading comprehension and expression in the rTMS group than in the sham group. Regression analysis showed that the pre-treatment fractional anisotropy, axial diffusivity and apparent diffusion coefficient of the right AF significantly correlated with the expression abilities (R2 > 0.700, p < 0.044) and comprehension abilities (R2 > 0.702, p < 0.039) in the rTMS group. It was concluded that the right AF could be a predictor in language recovery induced by LF-rTMS after the injuries of primary language circuits.