Zaghloul Ahmed

Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress.

Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D.

Trans-spinal direct current stimulation modulates motor cortex-induced muscle contraction in mice

The present study investigated the effect of trans-spinal direct current (tsDC) on the firing rate, pattern, and amplitude of spontaneous activity of the tibial nerve and on the magnitude of cortically elicited triceps surae (TS) muscle contractions. The effect of combined tsDC and repetitive cortical electrical stimulation (rCES) on the amplitude of cortically elicited TS twitches was also investigated. Stimulation was applied by two disk electrodes (0.79 cm(2)): one was located subcutaneously over the vertebral column (T(10)-L(1)) and was used to deliver anodal DC (a-tsDC) or cathodal DC (c-tsDC) (density range: ± 0.64 to ± 38.2 A/m(2)), whereas the other was located subcutaneously on the lateral aspect of the abdomen and served as a reference. While the application of a-tsDC significantly increased the spike frequency and amplitude of spontaneous discharges compared with c-tsDC, c-tsDC made the spontaneous discharges more rhythmic. Cortically elicited TS twitches were depressed during a-tsDC and potentiated after termination. Conversely, cortically elicited TS twitches were enhanced during c-tsDC and depressed after termination. While combined a-tsDC and rCES produced similar effects as a-tsDC alone, combined c-tsDC and rCES showed the greatest increase in cortically elicited TS twitches. tsDC appears to be a powerful neurostimulation tool that can differentially modulate spinal cord excitability and corticospinal transmission.

Trans-spinal direct current enhances corticospinal output and stimulation-evoked release of glutamate analog, D-2,3-3H-aspartic acid

Trans-spinal direct current (tsDC) stimulation is a modulator of spinal excitability and can influence cortically elicited muscle contraction in a polarity-dependent fashion. When combined with low-frequency repetitive cortical stimulation, cathodal tsDC [tsDC(-)] produces a long-term facilitation of cortically elicited muscle actions. We investigated the ability of this combined stimulation paradigm to facilitate cortically elicited muscle actions in spinal cord-injured and noninjured animals. The effect of tsDC-applied alone or in combination with repetitive spinal stimulation (rSS) on the release of the glutamate analog, D-2,3-(3)H-aspartate (D-Asp), from spinal cord preparations in vitro-was also tested. In noninjured animals, tsDC (-2 mA) reproducibly potentiated cortically elicited contractions of contralateral and ipsilateral muscles tested at various levels of baseline muscle contraction forces. Cortically elicited muscle responses in animals with contusive and hemisectioned spinal cord injuries (SCIs) were similarly potentiated. The combined paradigm of stimulation caused long-lasting potentiation of cortically elicited bilateral muscle contraction in injured and noninjured animals. Additional analysis suggests that at higher baseline forces, tsDC(-) application does not increase the rising slope of the muscle contraction but causes repeated firing of the same motor units. Both cathodal and anodal stimulations induced a significant increase of D-Asp release in vitro. The effect of the combined paradigm of stimulation (tsDC and rSS) on the concentration of extracellular D-Asp was polarity dependent. These results indicate that tsDC can powerfully modulate the responsiveness of spinal cord neurons. The results obtained from the in vitro preparation suggest that the changes in neuronal excitability were correlated with an increased concentration of extracellular glutamate. The combined paradigm of stimulation, used in our experiments, could be noninvasively applied to restore motor control in humans with SCI.

Effects of Cathodal Trans-Spinal Direct Current Stimulation on Mouse Spinal Network and Complex Multijoint Movements

Cathodal trans-spinal direct current (c-tsDC) stimulation is a powerful technique to modulate spinal excitability. However, the manner in which c-tsDC stimulation modulates cortically evoked simple single-joint and complex multijoint movements is unknown. To address this issue, anesthetized mice were suspended with the hindlimb allowed to move freely in space. Simple and complex multijoint movements were elicited with short and prolonged trains of electrical stimulation, respectively, delivered to the area of primary motor cortex representing the hindlimb. In addition, spinal cord burst generators are known to be involved in a variety of motor activities, including locomotion, postural control, and voluntary movements. Therefore, to shed light into the mechanisms underlying movements modulated by c-tsDC stimulation, spinal circuit activity was induced using GABA and glycine receptor blockers, which produced three rates of spinal bursting activity: fast, intermediate, and slow. Characteristics of bursting activity were assessed during c-tsDC stimulation. During c-tsDC stimulation, significant increases were observed in (1) ankle dorsiflexion amplitude and speed; (2) ankle plantarflexion amplitude, speed, and duration; and (3) complex multijoint movement amplitude, speed, and duration. However, complex multijoint movement tracing showed that c-tsDC did not change the form of movements. In addition, spinal bursting activity was significantly modulated during c-tsDC stimulation: (1) fast bursting activity showed increased rate, amplitude, and duration; (2) intermediate bursting activity showed increased rate and duration, but decreased amplitude; and (3) slow bursting activity showed increased rate, but decreased duration and amplitude. These results suggest that c-tsDC stimulation amplifies cortically evoked movements through spinal mechanisms.

Electrophysiological Characterization of Spino-Sciatic and Cortico-Sciatic Associative Plasticity: Modulation by Trans-Spinal Direct Current and Effects on Recovery after Spinal Cord Injury in Mice

Associative stimulation causes enduring changes in the nervous system based on the Hebbian concept of spike-timing-dependent plasticity. The present study aimed to characterize the immediate and long-term electrophysiological effects of associative stimulation at the level of spinal cord and to test how trans-spinal direct current stimulation (tsDC) modulates associative plasticity. The effect of combined associative stimulation and tsDC on locomotor recovery was tested in a unilateral model of spinal cord injury (SCI). Two associative protocols were tested: (1) spino-sciatic associative (SSA) protocol, in which the first stimulus originated from the sciatic nerve and the second from the spinal cord; and (2) cortico-sciatic associative (CSA) protocol, in which the first stimulus originated from the sciatic nerve and the second from the motor cortex. In addition, those two protocols were repeated in combination with cathodal tsDC application. SSA and CSA stimulation produced immediate enhancement of spinal and cortical outputs, respectively, depending on the duration of the interstimulus interval. Repetitive SSA or CSA stimulation produced long-term potentiation of spinal and cortical outputs, respectively. Applying tsDC during SSA or CSA stimulation markedly enhanced their immediate and long-term effects. In behaving mice with unilateral SCI, four consecutive 20 min sessions of CSA + tsDC markedly reduced error rate in a horizontal ladder-walking test. Thus, this form of artificially enhanced associative connection can be translated into a form of motor relearning that does not depend on practice or experience.

Combined Effects of Acrobatic Exercise and Magnetic Stimulation on the Functional Recovery after Spinal Cord Lesions

The objective of the study was to determine whether physical exercise combined with epidural spinal cord magnetic stimulation could improve recovery after injury of the spinal cord. Spinal cord lesioning in mice resulted in reduced locomotor function and negatively affected the muscle strength tested in vitro. Acrobatic exercise attenuated the behavioral effects of spinal cord injury. The exposure to magnetic fields facilitated further this improvement. The progress in behavioral recovery was correlated with reduced muscle degeneration and enhanced muscle contraction. The acrobatic exercise combined with stimulation with magnetic fields significantly facilitates behavioral recovery and muscle physiology in mice following spinal cord injury.

Trans-Spinal Direct Current Stimulation Alters Muscle Tone in Mice with and without Spinal Cord Injury with Spasticity

Muscle tone abnormalities are associated with many CNS pathologies and severely limit recovery of motor control. Muscle tone depends on the level of excitability of spinal motoneurons and interneurons. The present study investigated the following hypotheses: (1) direct current flowing from spinal cord to sciatic nerve [spinal-to-sciatic direct current stimulation (DCS)] would inhibit spinal motor neurons and interneurons, hence reducing muscle tone; and (2) direct current flowing in the opposite direction (sciatic-to-spinal DCS) would excite spinal motor neurons and interneurons, hence increasing muscle tone. Current intensity was biased to be ∼170 times greater at the spinal column than at the sciatic nerve. The results showed marked effects of DCS on muscle tone. In controls and mice with spinal cord injuries with spasticity, spinal-to-sciatic DCS reduced transit and steady stretch-induced nerve and muscle responses. Sciatic-to-spinal DCS caused opposite effects. These findings provide the first direct evidence that trans-spinal DCS can alter muscle tone and suggest that this approach could be used to reduce both hypotonia and hypertonia.

Trans-spinal direct current stimulation modifies spinal cord excitability through synaptic and axonal mechanisms

The spinal cord is extremely complex. Therefore, trans‐spinal direct current stimulation (tsDCS) is expected to produce a multitude of neurophysiological changes. Here, we asked how tsDCS differentially affects synaptic and nonsynaptic transmission. We investigated the effects of tsDCS on synaptically mediated responses by stimulating the medullary longitudinal fascicle and recording responses in the sciatic nerve and triceps and tibialis anterior muscles. Response amplitude was increased during cathodal‐tsDCS (c‐tsDCS), but reduced during anodal‐tsDCS (a‐tsDCS). After‐effects were dependent on the frequency of the test stimulation. c‐tsDCS‐reduced responses evoked by low‐frequency (0.5 Hz) test stimulation and increased responses evoked by high‐frequency (400 Hz) test stimulation. a‐tsDCS had opposite effects. During and after c‐tsDCS, excitability of the lateral funiculus tract (LFT) and dorsal root fibers was increased. However, a‐tsDCS caused a complex response, reducing the excitability of LFT and increasing dorsal root fiber responses. Local DC application on the sciatic nerve showed that the effects of DC on axonal excitability were dependent on polarity, duration of stimulation, temporal profile (during vs. after stimulation), orientation of the current direction relative to the axon and relative to the direction of action potential propagation, distance from the DC electrode, and the local environment of the nervous tissue. Collectively, these results indicate that synaptic as well as axonal mechanisms might play a role in tsDCS‐induced effects. Therefore, this study identified many factors that should be considered in interpreting results of DCS and in designing tsDCS‐based interventions.

Pulsed magnetic stimulation modifies amplitude of action potentials in vitro via ionic channels-dependent mechanism.

This paper investigates the influence of pulsed magnetic fields (PMFs) on amplitude of evoked, compound action potential (CAP) recorded from the segments of sciatic nerve in vitro. PMFs were applied for 30 min at frequency of 0.16 Hz and intensity of 15 mT. In confirmation of our previous reports, PMF exposure enhanced amplitude of CAPs. The effect persisted beyond PMF activation period. As expected, CAP amplitude was attenuated by antagonists of sodium channel, lidocaine, and tetrodotoxin. Depression of the potential by sodium channels antagonists was reversed by subsequent exposure to PMFs. The effect of elevated potassium concentration and veratridine on the action potential was modified by exposure to PMFs as well. Neither inhibitors of protein kinase C and protein kinase A, nor known free radicals scavengers had any effects on PMF action. Possible mechanisms of PMF action are discussed.

Activity-Dependent Axonal Plasticity: The Effects of Electrical Stimulation on Compound Action Potentials Recorded from the Mouse Nervous System In Vitro

The influence of electrical stimulation on the amplitude of the action potentials recorded from the mouse nerv- ous system in vitro was investigated. Brief (1 s) high frequency (100 Hz) stimulation of the sciatic nerve induced a long- lasting increase in the amplitude of the compound action potential (CAP). Low frequency (1 Hz) stimulation delivered for 15 min attenuated the antidromically evoked potential recorded from hippocampal slices and CAP recorded from the sci- atic nerve. The stimulation-induced decrease in the amplitude of CAP occurred in two phases. While during the first phase the decrease was reversible and calcium-dependent, the second, later phase was irreversible. The experiments with two stimulating electrodes activated separately revealed that the changes in the CAP amplitude were not related to unspecific electrode-tissue interactions. The attenuation in the CAP amplitude was accompanied by an increase and decrease of minimal and maximal thresholds, respectively. The stimulation of the sciatic nerve segments with twin pulses revealed that the velocity of CAP propagation and refractoriness were significantly diminished after LFS application. The stimula- tion-induced changes in CAP were correlated with decreased sodium channels antibody signal, indicating fall in the num- ber of sodium channels. According to postulated hypothesis, the stimulation-induced influx of Na + during the first phase intensifies internalization of sodium channels. This amplified endocytosis is accompanied by activation of lysosomal pathways and subsequent hydrolysis of sodium channels leading to irreversible decline in the CAP amplitude. Described results indicate, that axons can contribute to neuronal plasticity.