Decrease In Conduction Velocity Research Articles

Effect of Chronic Consumption of Fluoridated Water on Sciatic Nerve Conduction Velocity in Male Wistar Rats.

The long-term effect of fluoridated water consumption during development on the velocity of nerve impulse conduction in the sciatic nerve of rats was assessed. Thirty male Wistar rats, 21 days old, were randomly assigned to five groups. Three groups were given fluoridated water ad libitum (as the only source) at different concentrations (10, 100, and 150 ppm), designated as groups F10, F100, and F150, respectively. The study included a control group (C) that received fluoridated water at the maximum level established by the World Health Organization (1.5 ppm of fluorides) and another group that received deionized water (DW). The animals were treated until they reached 90 days of age. Electrophysiological recordings were performed on the rats' sciatic nerves to determine nerve conduction velocity, and blood plasma was extracted for fluoride concentration analysis. The study found that the F150 group had a lower nerve impulse conduction velocity in the sciatic nerve compared to the C group (P = 0.0015). Additionally, there was a negative correlation between the concentration of fluorides in plasma and the nerve conduction velocity (r = -0.5132, P = 0.0037). These findings indicate that chronic consumption of high concentrations of fluoride leads to a decrease in nerve conduction velocity. This, in conjunction with potential alterations in the central nervous system, may explain the deficits in learning and memory tests that have been documented in numerous studies evaluating individuals exposed to fluoride consumption. These results provide valuable information for understanding the effects and action mechanisms of fluoride in exposed individuals.

Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton. Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of SYNE2α1. After SYNE2 knockdown or SYNE2α1 overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity. The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short SYNE2α1 isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 overexpression had dominant negative effects on the nucleus with its overexpression or SYNE2 knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from SYNE2α1 overexpression demonstrated both concordant and nonconcordant effects with SYNE2 knockdown. SYNE2α1 overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while SYNE2 knockdown showed both shortened assessed action potential duration and decreased conduction velocity. rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing SYNE2α1 expression. Downstream effects of SYNE2α1 overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF.

Hereditary spastic paraplegia and extensive leukoencephalopathy: a case report of a unique phenotype associated with a GJB1/Cx32 p.Pro174Ser variant

BackgroundPathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations.Case presentationA 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser.ConclusionsThe patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

Schwann cell-derived exosomes ameliorate peripheral neuropathy induced by ablation of dicer in Schwann cells.

MicroRNAs (miRNAs) in Schwann cells (SCs) mediate peripheral nerve function. Ablating Dicer, a key gene in miRNA biogenesis, in SCs causes peripheral neuropathy. Exosomes from healthy SCs (SC-Exo) ameliorate diabetic peripheral neuropathy in part via miRNAs. Thus, using transgenic mice with conditional and inducible ablation of Dicer in proteolipid protein (PLP) expressing SCs (PLP-cKO), we examined whether SC-Exo could reduce peripheral neuropathy in PLP-cKO mice. PLP-cKO mice at the age of 16 weeks (8 week post-Tamoxifen) were randomly treated with SC-Exo or saline weekly for 8 weeks. Age-and sex-matched wild-type (WT) littermates were used as controls. Peripheral neurological functions, sciatic nerve integrity, and myelination were analyzed. Quantitative RT-PCR and Western blot analyses were performed to examine miRNA and protein expression in sciatic nerve tissues, respectively. Compared to the WT mice, PLP-cKO mice exhibited a significant decrease in motor and sensory conduction velocities, thermal sensitivity, and motor coordination. PLP-cKO mice exhibited substantial demyelination and axonal damage of the sciatic nerve. Treatment of PLP-cKO mice with SC-Exo significantly ameliorated the peripheral neuropathy and sciatic nerve damage. PLP-cKO mice showed a substantial reduction in a set of Dicer-related miRNAs known to regulate myelination, axonal integrity, and inflammation such as miR-138, -146a and - 338 in the sciatic nerve. In addition, PLP-cKO mice exhibited significant reduction of myelin forming proteins, early growth response 2 (EGR2) and sex determining region Y-box10 (Sox10), but significantly increased myelination inhibitors, Notch1, c-Jun, and Sox2 and the axonal growth inhibitor phosphatase and tens in homolog (PTEN). However, SC-Exo treatment reversed the PLP-cKO altered miRNAs and proteins. This study demonstrates that exogenous SC-Exo ameliorate peripheral neuropathy induced by Dicer ablation in PLP expressing SCs. The therapeutic benefit may be mediated by the SC-Exo altered miRNAs and their targeted genes.

Blocking Aδ- and C-fiber neural transmission by sub-kilohertz peripheral nerve stimulation.

We recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS). We explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz. Suprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50-1000 Hz stimulation and C-fibers blocked by 10-50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS. The current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (<100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders.

Bioenergetics and mitochondrial deregulation underlie self-sustained persistency of atrial fibrillation in an ovine model

Abstract Background Atrial fibrillation (AF) often transitions from paroxysmal to more sustained forms in a 4-15/100 person-year range(1). It is well-recognized from both clinical and animal studies that some individuals undergo this transition much more readily than others, but the underlying mechanisms remain unclear. Purpose To identify potential differences in atrial bioenergetics between animals developing stable AF (AF-S) versus those resistant to this transition (AF-R) in a sheep AF-model. Methods AF was induced through repeated bursts of atrial tachystimulation (2). Stability of AF was monitored with telemetry. In-vivo electrophysiological remodeling was assessed via contact mapping. Metabolic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Results AF-S sheep developed stable (&amp;gt;24-hour self-sustained) AF after 13 (range 5-22) days on average, whereas AF-R sheep failed to develop stable AF despite 120-day tachystimulation. Contact mapping and histological analysis revealed similar electro-anatomical remodeling in AF-S and AF-R groups, with the only significant difference observed in the decrease of activation time and conduction velocity in the AF-S atria. Both AF-S and AF-R animals displayed a notable increase in mitochondrial mass. Proteomic analysis showed significant differences in metabolism-related proteins and pathways between AF-S and AF-R, in particular concerning the anaplerotic supplementation of the tricarboxylic acid cycle at the level of α-ketoglutarate. Furthermore, compared to AF-R, AF-S LAA exhibited a 45% increase in succinate content, and a 23% decrease in ATP and Creatine Phosphate (PCr) content, suggesting a pathological metabolic alteration linked to a bioenergetic default. AF-S mitochondria presented abnormal succinate-oxidation, associated with a significant 20% decrease in ATP-synthesis rate, 22% increase in ROS-production, mitochondrial-membrane hyperpolarization, and decreased Complex I/II specific activity ratio. AF-S mitochondria alterations were prevented by complex I inhibitor S1QEL1.1, hinting to a participation of mitochondrial ROS into the mechanism of AF stabilization. In vivo acute intravenous perfusion of succinate in rats made them more susceptible to more frequent (OR 35 CI=[1.63-449.80]) and longer AF episodes upon treansesophageal stimulation; this vulnerability to AF was prevented by intraperitoneal pretreatment with SQEL1.1. Conclusions Resistance to AF-stabilization is associated with specific bioenergetic remodeling. These findings provide new mechanistic insights into AF-resistance and might open avenues for novel therapeutic strategies for AF-management.

Correlation and influencing factors of neurophysiological examinations and serum uric acid in patients with diabetic peripheral neuropathy: an exploratory study

Objective This study aimed to investigate the correlation and influencing factors between neurophysiological examinations, serum uric acid (SUA), and glucose metabolism in patients with Diabetic Peripheral Neuropathy (DPN). Methods A total of 114 patients with DPN who received treatment at the Endocrinology Department of our hospital from January 2022 to December 2023 were included. According to the median blood uric acid level, the patients were divided into high SUA group and low SUA group, and the demographic data, blood glucose indexes and motor nerve electrophysiological examination results of the two groups were compared. Results The level of FPG and HbA1c was higher in the high SUA group. The motor nerve latency of the high SUA group was higher, the motor nerve amplitude and motor nerve conduction velocity of the high SUA group were lower than those of the low SUA group. SUA was positively correlated with motor nerve latency and negatively correlated with motor nerve amplitude and conduction velocity. Conclusion In DPN, high SUA levels are associated with poor glycemic control. With the increase in SUA levels, the motor nerve latency in patients with T2DM is prolonged, and amplitude and conduction velocity decrease, and high SUA is a risk factor and potential predictor of DPN.

Electrophysiological variations of Guillain-Barre syndrome in Bangladesh- Hospital based study

Introduction: Guillain-Barre syndrome (GBS) is an immune mediated disorder of peripheral nerves which usually presents by rapidly evolving ascending weakness &amp; mild sensory loss and hypo- or areflexia. Electrodiagnostic study (EDS) is the basis for classification of different subtypes of the disease. EDS also has a crucial role in diagnosis, ruling out of some differential diagnosis like myopathic and motor neuron disorders and confirming the neuropathic nature of GBS. The benefit of immunotherapy is greatest when introduced early. In addition, electrophysiological characteristic can predict the prognosis of patients with GBS. This study was conducted to determine the predominant subtype and electrophysiological pattern of GBS in the context of Bangladesh. Objectives: Objective of this study was to compare the electrophysiological variations among different electrophysiological subtypes of GBS. Methods: It is an observational cross sectional study conducted in Department of Medicine and Neurology, Sir Salimullah Medical College &amp; Mitford Hospital and National Institute of Neuroscience (NINS), Dhaka, over a period of one year &amp; four months. Total 30 patients were selected by purposive sampling technique. Demographic data were collected from the patients and recorded in structured case report form. Clinical examination and relevant investigations were done meticulously. Collected questionnaire were checked to identify any error in data. Data was analyzed with SPSS version 21 software. Result: In this study, maximum numbers of patients 53% were between 21-30 years of age group with mean value 27.47±8.1 years. Male to female ratio was 1.7:1. Frequency of Guillain-Barre syndrome is predominance at middle age group. Commonest presentation was limb weakness (parapledgia or quadripledgia) in 60% patients, paresthesias &amp; numbness (40%), pain (100%) and deviation of mouth (63%) of GBS patients. Cerebrospinal fluid shows a mild pleocytosis (5 to 50 cells/µl) in majority of cases was found in 76% of patients. Whereas elevated CSF Protein (&gt;45 mg/dl) was seen in all GBS patient. Increased distal motor latency (DML) was found in 93% patients, whereas 7% patients had normal DML. In the case of the lower limbs, increased distal motor latency was predominant. Decreased amplitude of sensory nerve action potential (SNAP) was seen in 83% patients while 16% patients had normal. Slowing of motor conduction velocities, decreased amplitude as well as increase in distal motor latencies were observed, being more pronounced in the lower limbs. F-wave was completely absent in 20.0% patients while 20% patients showed decreased conduction velocity with prolonged latency. Sensory nerve action potential revealed that decreased sensory conduction velocity (SCV) was seen in 26%, absent SCV in 10% and normal SCV in 63% patients. Present study demonstrated that Acute inflammatory demyelinating polyneuropathy (AIDP) was the commonest type of Guillain-Barré syndrome, present in 56% of patient. Around 30% of the patients belonged to acute motor axonal polyneuropathy (AMAN) and 13% were acute motor sensory axonal polyneuropathy (AMSAN). Conclusion: In this study AIDP was the most frequent subtype. The characteristic findings supportive of AIDP include prolonged distal motor latencies, reduced conduction velocities, conduction blocks at non-entrapment sites, temporal dispersion and prolonged F wave latencies. J MEDICINE 2024; 25: 11-16

Proximal and Distal Nerve Conduction Studies in Carpal Tunnel Syndrome

Introduction/Aims: The exact reason for the decrease in median nerve motor conduction velocity (MMCV) in the forearm in carpal tunnel syndrome (CTS) is debatable. However, some studies support the hypothesis of blockage of large, myelinated fibers in the carpal tunnel, and/or retrograde axonal degeneration. We aimed to determine the decrease in the MMCV of the second lumbrical (FMMCVL) and abductor pollicis brevis (APB) muscles recorded in the forearm (FMMCVAPB) in patients with CTS compared with a control group and also to compare the MMCV among CTS subgroups with different severity. Methods: The study included data on the hands of 51 patients and 20 volunteer controls. Patients were divided into four groups according to the severity of the involvement, minimal, mild, moderate, and severe. Routine median, ulnar, and comparative conduction studies were performed. By stimulating the median nerve at the palm, wrist, and elbow, responses were recorded over the APB and second lumbrical muscles. MMCV was assessed in the transcarpal segment (TCMMCV) and forearm. Results: The mean FMMCVAPB and FMMCVL in patients were 53.8 ± 4.2 m/s and 54.3 ± 5.6 m/s, respectively, and were significantly slower than in the controls (P &lt; 0.001 and P = 0.012, respectively). The FMMCVL was significantly decreased in the severe group compared with the other three groups (P &lt; 0.001). FMMCVL and FMMCVAPB relatively decreased as CTS severity increased. Conclusion: In this study, FMMCVAPB and FMMCVL were found significantly slower. Slowing of FMMCVL in the forearm is related to the severity of CTS. The decrease in MMCV in the forearm did not parallel the decrease in TCMMCV. This suggests that retrograde axonal degeneration may be the contributing factor to forearm slowing. There is also an association between axonal degeneration and disease severity.

The role of MAPRE2 and microtubules in Brugada syndrome pathogenesis

Abstract Background Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), which are found in only ∼20% of patients. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), implicating microtubule (MT) involvement in BrS. Purpose To understand the role of MAPRE2 and MT in BrS pathogenesis. Methods A mapre2 knock-out (KO) zebrafish model was generated using CRISPR/Cas9 and validated by western blot. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry with confocal imaging. Morpholino targeting mapre2 or ttl (encoding tubulin tyrosine ligase) were injected into zebrafish embryos at the one-cell stage. A transgenic zebrafish line with cdh2 (encoding N-cadherin) tandem fluorescent timer (tFT) was used to study adherens junction. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes (CM) with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Results Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p&amp;lt;0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p&amp;lt;0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p&amp;lt;0.0001). Confocal imaging of KO hearts showed disorganized adherens junction based on N-cadherin staining. Similarly, morpholino KD of mapre2 in the cdh2 tFT line showed ∼40% mislocalization of mature N-cadherin relative to ZO-1 staining in larval ventricles (8 KDs vs 9 control hearts; p&amp;lt;0.05), suggesting disruption of adherens junction. In terms of MT, immunohistochemistry showed a 23% decrease of detyrosinated tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p&amp;lt;0.01). MAPRE2 KD in iPSC-CM (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 µm/min; p&amp;lt;0.001), distance (5.8±0.2 vs. 7.1±0.2 µm; p&amp;lt;0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p&amp;lt;0.001), suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of detyrosinated tubulin (46% increase; 16 controls vs. 16 KDs; p&amp;lt;0.01) as well as Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p&amp;lt;0.01) to WT levels. Conclusion Genetic ablation of mapre2 led to a decrease in cardiac NaV function, a hallmark of BrS. This is associated with disruption of adherens junction, a decrease of detyrosinated tubulin as a marker of MT stability, and changes in MT dynamics. Restoration of detyrosinated tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis by disruption of adherens junction via changes in MT dynamics.

Abstract 15242: The Flipside of Flecainide: A Case of Flecainide Induced Loss of Capture

Introduction: Flecainide is a class 1c anti-arrhythmic agent that slows phase 0 of the fast inward sodium (Na) channels in a rate-dependent fashion leading to decreased conduction velocity in the His-Purkinje and ventricular myocardium. Its high affinity and slow unbinding prolong QRS duration on electrocardiogram (EKG). Partial renal excretion and a narrow therapeutic index of 0.2-1mcg/mL can cause drug toxicity. Case: A 72-year-old woman presented with palpitations and weakness. She had a history of non-ischemic cardiomyopathy, biventricular (BiV) implantable cardioverter defibrillator, frequent premature ventricular contractions on flecainide 100 mg twice a day, and chronic kidney disease. She was hypotensive and with acute kidney injury. EKG showed wide complex ventricular rhythm, QRS duration of 305 ms and intermittent ventricular pacing (Fig.1A), changed since EKG 6 months ago (Fig.1B). Device interrogation revealed normal sensing and impedances but failure to capture from all 3 leads. She had stable lead parameters and appropriate BiV pacing 6 months ago. Chest X ray showed stable lead positions. Flecainide toxicity was suspected, and Na bicarbonate infusion was started. Flecainide level was 2.4mcg/mL (normal &lt;1mcg/mL). She went into an idioventricular rhythm which terminated spontaneously (Fig.1C). After 48 hours of Na bicarbonate infusion, lead capture was noted with narrower QRS (198 ms) (Fig.1D) and on day 6, EKG was back to effective BiV pacing with QRS duration 127 ms (Fig.1E). Discussion: This case highlights the EKG manifestations of flecainide toxicity including QRS widening, sine-wave pattern and loss of pacing capture due to prolonged ventricular refractoriness. It also underscores the reversibility of this condition with prompt treatment using Na bicarbonate. Conclusion: Early recognition and rapid treatment of the cardiac effects of flecainide toxicity is critical in managing a life threatening but reversible medical condition.

Trunk extensor muscle endurance and its relationship to action potential conduction velocity and spectral parameters estimated using high-density electromyography

Trunk extensor muscle fatigue typically manifests as a decline in spectral content of surface electromyography. However, previous research on the relationship of this decline with trunk extensor muscle endurance have shown inconsistent results. The decline of spectral content mainly reflects the decrease in average motor unit action potential conduction velocity (CV). We evaluated whether the rate of change in CV, as well as two approaches employing the change in spectral content, are related to trunk extensor muscle endurance. Fourteen healthy male participants without a low-back pain history performed a non-strictly controlled static forward trunk bending trial until exhaustion while standing. For 13 participants, physiologically plausible CV estimates were obtained from high-density surface electromyography bilaterally from T6 to L5. Laterally between L1 and L2, the linear rate of CV change was strongly correlated to endurance time (R2 = 0.79), whereas analyses involving the linear rate of change in spectral measures showed a lower (R2 = 0.38) or no correlation. For medial electrode locations, estimating CV and its relationship with endurance time was less successful, while the linear rate of change in spectral measures correlated moderately to endurance time (R2 = 0.44; R2 = 0.56). This study provides guidance on monitoring trunk extensor muscle fatigue development using electromyography.

Motor Activity-Induced White Matter Repair in White Matter Stroke.

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery.

Association of Sensory Nerve Action Potential Amplitude and Velocity With Type 2 Diabetic Peripheral Neuropathy.

There is ongoing controversy regarding the predominant type of nerve injury in diabetic peripheral neuropathy, whether it is demyelination or axonal degeneration. This study aimed to investigate the association between nerve conduction study parameters, specifically nerve conduction velocity and the amplitude of the action potential, with diabetic peripheral neuropathy and determine their potential as early indicators of the condition. A cross-sectional study was conducted involving diagnosed type 2 diabetes mellitus patients, who were divided into two groups: Group I (n = 111) with symptomatic diabetic peripheral neuropathy and Group II (n = 109) without clinically detectable peripheral neuropathy. Age and sex-matched healthy controls (n = 100) were also included. Nerve conduction velocity measurements were performed on both upper and lower limbs, with motor nerve conduction study focusing on the dominant side using the median and posterior tibial nervesand sensory nerve conduction study using the median and sural nerves. The nerve conduction studies revealed significantly lower sensory nerve action potential amplitudes and compound muscle action potential amplitudes in the median, posterior tibial, and sural nerves of the diabetic groups compared to the control subjects. Furthermore, these changes were more prominent in patients with peripheral neuropathy. Among the 220 diabetic patients analyzed, 135 (61.36%) exhibited nerve conduction abnormalities. The highest rate of abnormality was observed in the sural nerve, followed by the posterior tibial and median nerves. The most common abnormality detected in diabetic patients was a decrease in sensory nerve action potential, followed by a decrease in sensory nerve conduction velocity. The study findings suggest an association between reduced sensory nerve action potential amplitude and diabetic peripheral neuropathy. These results highlight the potential of sensory nerve action potential and velocity as a sensitive indicator of peripheral neuropathy in diabetic patients.

Abstract P2164: Expression Of Engineered Bacterial Sodium Channel Improves Cardiomyocyte Contractility

Introduction: Our recent studies in non-human primates have demonstrated adeno-associated virus (AAV) delivery of prokaryotic sodium channel (BacNa v ) can improve the contractile function of infarcted hearts. We hypothesized that BacNa v expression increases cardiomyocyte (CM) contractile function by indirectly augmenting Ca 2+ transient amplitude via increase in sarcoplasmic reticulum (SR) Ca 2+ stores. Methods: We developed an in vitro model of ischemia-reperfusion (I/R) injury in engineered heart tissues (cardiopatches) made from human iPSC-derived CMs (hiPSC-CMs). Prior to formation, tissues were transduced with lentivirus conferring a doxycycline (Dox)-inducible expression of BacNa v . Upon I/R injury, the tissues were treated with either vehicle or Dox for 48h followed by force testing and Ca 2+ imaging. The effect of BacNa v expression on Ca 2+ handling was additionally studied using neonatal rat ventricular myocytes (NRVMs). Results: The tissue injury from I/R was evident from increases in cleaved-caspase 3 area (0.25% vs 1.53%), ROS generation (1.2 fold), LDH release (4.1 fold), and percent dead cells (0.97% vs 4.67%). Immediately following the I/R injury, tissues showed decrease in contractile force (2.78mN vs 0.74mN) and conduction velocity (20.7cm/s vs 7.9cm/s). At 72hr post-injury, BacNa v -expressing tissues exhibited significantly higher contractile force (1.67mN vs 1.32mN) and Ca 2+ transient (1.8 fold) amplitudes compared to the vehicle control. Furthermore, in uninjured NRVM monolayers, BacNa v expression resulted in higher Ca 2+ transient amplitude (1.31 fold), as well as increased SR calcium stores (1.3 fold) and slower sodium/calcium exchanger (NCX) extrusion rate (1.03s -1 vs 0.82s -1 ) in the presence of caffeine. Blocking NCX with 10M ORM-10962 eliminated the difference in Ca 2+ transient amplitude between BacNa v -expressing and control CMs. Conclusion: Our results suggest BacNa v expression augments CM contractility and Ca 2+ transient amplitude, at least in part through the suppression of Ca 2+ efflux mode of the NCX. In addition to its antiarrhythmic effects, BacNa v gene delivery may represent an effective therapeutic strategy to improve cardiac contractility in congestive heart failure.

Electrophysiological assessment of patients recovered from COVID-19 infection

Background: Neurological manifestation associated with Coronavirus-19 (COVID-19) is commonly reported. However, these patients were not routinely referred for electrophysiological testing. Many studies reported abnormalities in nerve conduction studies (NCS) in patients who recovered from COVID-19 infection. Aim: we aimed to investigate the effect of COVID-19 infection on patients who performed NCS prior to the COVID-19 pandemic and after recovering from COVID-19 illness. Methods: A cohort retrospective study was conducted, which included males and females (average age 50.6 years old) participants who performed NCS before the pandemic and were not hospitalized during their COVID-19 illness. We assessed sensory and motor NCS for the ulnar, median, peroneal, tibial, and sural nerves. A total of 14 ulnar and median nerves and six tibial, peroneal, and sural nerves were assessed. Results: All tested parameters were normal in most of our participants. However, there was a significant increase in amplitude and decrease in conduction velocity (CV) in sensory NCS in median nerves ( p &lt;0.005) and ulnar nerves ( p &lt;0.05). There is an increase in amplitudes and a decrease in the CV in the lower limbs' sensory and motor NCS and the motor ulnar and median nerves, but this did not reach a significance level. Conclusion: This is the first study to assess the effect of COVID-19 on the same nerves (before and after COVID-19 infection). Although all NCS parameters were normal, the paired analysis showed that the median and ulnar sensory nerves are the most affected by COVID-19. Standardized electrodiagnostic guidelines are recommended to be established for recovered COVID-19 patients for early diagnosis of neural functions to ensure optimal recovery. This research was not funded. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PO-02-153 THE ROLE OF MAPRE2 AND MICROTUBULES IN CARDIAC ELECTROPHYSIOLOGY AND BRUGADA SYNDROME

Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), yet these are only found in ∼20% of probands. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), which implicates microtubule (MT) involvement in BrS. To understand the role of MAPRE2 and MT in cardiac electrophysiology and BrS pathogenesis. Using CRISPR/Cas9, a mapre2 knock-out (KO) mutant was generated in zebrafish and validated by western blot. Morpholino targeting ttl (encoding tubulin tyrosine ligase) was injected into zebrafish embryos at the one-cell stage. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p<0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p<0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p<0.0001). Immunohistochemistry showed a 23% decrease of detyrosinated (glu) tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p<0.01). MT plus-end tracking experiments (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 μm/min; p<0.001), distance (5.8±0.2 vs. 7.1±0.2 μm; p<0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p<0.001) with MAPRE2 KD, suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of glu-tubulin (46% increase; 16 controls vs. 16 ttl KDs; p<0.01) and Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p<0.01) to WT levels. Genetic ablation of mapre2 led to a decrease in NaV function, a hallmark of BrS. This is associated with a decrease in glu-tubulin as a marker of MT stability and changes in MT dynamics. Restoration of glu-tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis via a novel paradigm of disrupting MT stability and dynamics.

Appearance of F-wave during electrophysiological study of

To evaluate the appearance of F-wave in patients with carpal tunnel syndrome through electrophysiological study. Fifty patients with carpal tunnel syndrome(CTS) of the median nerve who were diagnosed clinically and through electrophysiological study for median and ulnar nerve. Fifty normal subjects of healthy volunteers of similar age and gender were compared to the patients and examined for nerve conduction study. Nerve conduction study for median and ulnar nerve (motor and sensory) were done for each patient and subject in neurophysiology department to study the distal motor and sensory latency (DML,DSL), compound motor and sensory action potentials (CMAP,SNAP) ,motor and sensory nerve conduction velocities (MNCV,SNCV) and F-wave latencies(maximum, mean and minimum). There are prolonged distal motor and sensory latency, decrease of compound motor and sensory action potential, decrease of motor and sensory nerve conduction velocity and prolongation of F-wave latencies( minimum, mean and maximum.) of the median nerve (motor) in carpal tunnel syndrome patients compared with the controls and these differences are statistically significant p-value &lt; 0.01. The F-wave parameters for median nerve must be added in electrophysiological study to establish the diagnosis of carpal tunnel syndrome.

Inhibition of EPAC1 signaling pathway alters atrial electrophysiology and prevents atrial fibrillation.

Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with increased mortality and morbidity. The Exchange Protein directly Activated by cAMP (EPAC), has been implicated in pro-arrhythmic signaling pathways in the atria, but the underlying mechanisms remain unknown. Methods: In this study, we investigated the involvement of EPAC1 and EPAC2 isoforms in the genesis of AF in wild type (WT) mice and knockout (KO) mice for EPAC1 or EPAC2. We also employed EPAC pharmacological modulators to selectively activate EPAC proteins (8-CPT-AM; 10μM), or inhibit either EPAC1 (AM-001; 20μM) or EPAC2 (ESI-05; 25μM). Transesophageal stimulation was used to characterize the induction of AF in vivo in mice. Optical mapping experiments were performed on isolated mouse atria and cellular electrophysiology was examined by whole-cell patch-clamp technique. Results: In wild type mice, we found 8-CPT-AM slightly increased AF susceptibility and that this was blocked by the EPAC1 inhibitor AM-001 but not the EPAC2 inhibitor ESI-05. Consistent with this, in EPAC1 KO mice, occurrence of AF was observed in 3/12 (vs. 4/10 WT littermates) and 4/10 in EPAC2 KO (vs. 5/10 WT littermates). In wild type animals, optical mapping experiments revealed that 8-CPT-AM perfusion increased action potential duration even in the presence of AM-001 or ESI-05. Interestingly, 8-CPT-AM perfusion decreased conduction velocity, an effect blunted by AM-001 but not ESI-05. Patch-clamp experiments demonstrated action potential prolongation after 8-CPT-AM perfusion in both wild type and EPAC1 KO mice and this effect was partially prevented by AM-001 in WT. Conclusion: Together, these results indicate that EPAC1 and EPAC2 signaling pathways differentially alter atrial electrophysiology but only the EPAC1 isoform is involved in the genesis of AF. Selective blockade of EPAC1 with AM-001 prevents AF in mice.

A PROSPECTIVE STUDY FOR THE EVALUATION OF NERVE CONDUCTION ABNORMALITIES IN NEWLY DIAGNOSED TYPE 2 DIABETIC PATIENTS

Objectives: Peripheral neuropathy is the one of the frequently encountered complication of type 2 diabetes mellitus (T2DM). Although, the prevalence of diabetic peripheral neuropathy is associated with the diabetes duration, in some cases, the state of neuropathy is evident at the time of diagnosis. In this backdrop, the present study was carried out to evaluate the nerve conduction abnormalities in newly diagnosed T2DM. Methods: This was a prospective study carried out on 30 newly diagnosed T2DM within a time range of 1 month. The patient symptoms such as weakness, burning and tingling senzation, hyperesthesia, and foot ulcer and gait abnormalities were recorded. Nerve conduction analysis of upper limb and lower limb of non-dominant hand side was done using neuro pack S1 machine. Results: Thirty newly diagnosed T2DM patients were enrolled in the present study. The mean age of the patients was found to be 58.12±15.28 years. Distal motor latencies were elevated in T2DM patients as compared to the controls (p&lt;0.05). Further, there was significant prolongation of F-wave latencies in the upper and Lower limbs of the patients as compared to the controls (p&lt;0.05). In addition, there was a significant decrease in sensory conduction velocities in T2DM patients as that of the controls (p&lt;0.05). Conclusion: The study concludes that newly diagnosed T2DM is susceptible to DPN with high incidence rates. Hence, it is essential to perform the nerve conduction studies in newly diagnosed T2DM patients for the early detection and better management and also to prevent the complications.