DUAL-tDCS Treatment over the Temporo-Parietal Cortex Enhances Writing Skills: First Evidence from Chronic Post-Stroke Aphasia

The learning of writing skills involves the re-engagement of previously established independent procedures. Indeed, the writing deficit an adult may acquire after left hemispheric brain injury is caused by either an impairment to the lexical route, which processes words as a whole, to the sublexical procedure based on phoneme-to-grapheme conversion rules, or to both procedures. To date, several approaches have been proposed for writing disorders, among which, interventions aimed at restoring the sub-lexical procedure were successful in cases of severe agraphia. In a randomized double-blind crossover design, fourteen chronic Italian post-stroke aphasics underwent dual transcranial direct current stimulation (tDCS) (20 min, 2 mA) with anodal and cathodal current simultaneously placed over the left and right temporo-parietal cortex, respectively. Two different conditions were considered: (1) real, and (2) sham, while performing a writing task. Each experimental condition was performed for ten workdays over two weeks. After real stimulation, a greater amelioration in writing with respect to the sham was found. Relevantly, these effects generalized to different language tasks not directly treated. This evidence suggests, for the first time, that dual tDCS associated with training is efficacious for severe agraphia. Our results confirm the critical role of the temporo-parietal cortex in writing skills.

In vitro Passive and Iontophoretically Assisted Transport of Salbutamol sulphate through Hairless Mice Skin

Investigations were carried out to ascertain the relative importance of the described mechanism in iontophoretic transport using an ionizable drug salbutamol sulphate, which has two pKa values 9.3 (for amino group) and 10.3 (for phenolic group). Ionization of salbutamol sulphate varies with pH, hence the rate and extent of transport across the skin can be enhanced, controlled and manipulated by the application of factors like anodal and cathodal current at varied pH of donor solution and current densities. To determine these parameters, experiments were performed and data was collected at 7.4, 9.3, 10.3 and 11 pH using 4mg/ml drug concentration and 0.3mA/cm2 current density for 6 hours. After establishing the pH for optimum transport of drug, effect of current density (0.1, 0.2, 0.3 and 0.4 mA/cm2) on the transport of drug (keeping drug concentration constant) were investigated. Passive diffusion of salbutamol sulphate was maximal at pH 10.3 and 9.3, when unionized form of drug was 50%. Anodal iontophoresis at pH 7.4 was most effective (significant result, p < 0.05) in transport of drug across skin as compared to cathodal iontophoresis at pH 11. The effect of current density on steady state flux by salbutamol sulphate during anodal iontophoresis at 7.4 pH showed 2.26 and 28.05µg/cm2/h at 0.0 i.e., passive diffusion and 0.4 mA/cm2, respectively. Thus, flux was enhanced nearly 12 times during anodal iontophoresis.

Evaluation of Passive and Iontophoretic Transport of Lisinopril from Hydrogel Matrix Across Model Membrane In Vitro

Clinical studies of lisinopril delivery through iontophoresis are highly desired for better controls over transdermal drug flux. Therefore, investigations were carried out to ascertain the relative importance of the various factor for iontophoretic transport using an ionizable drug lisinopril, which has four pKa values 2.4, 4.0 (for amino group) and 6.7, 7.0 (for carboxylic group). Ionization of lisinopril varies with pH, hence rate and extent of transport across the skin can be enhanced, controlled and manipulated by the application of factors like anodal and cathodal current at varied pH of donor solution and current densities. To determine these parameters, experiments were performed and data were collected at 3.0, 4.0 and 7.4 pH using 4 mg/ml drug concentration and 0.1 mA/cm2 current density for 10 hours. After establishing the pH for optimum transport of drug, effect of current density (0.1, 0.2, 0.3 and 0.4 mA/cm2) on the transport of drug (keeping drug concentration constant) were investigated. Passive diffusion of lisinopril was maximal at pH 3.0, when unionized form of drug was 45%. Anodal iontophoresis was most effective (significant result, p less than 0.05) in transport of drug across skin as compared to cathodal iontophoresis at pH 3.0. While at pH 4.0, cathodal iontophoretic transport of lisinopril across rat skin was highly effective (Student‘t’ test, p less than 0.05) compared to anodal iontophoresis. The effect of current density on steady state flux of lisinopril during cathodal iontophoresis at 7.4 pH was 1.33 ± 1.12 and 24.8 ± 3.1 μg/cm2/h at 0.0 under passive diffusion and 4 mA/cm2, respectively. Thus, flux was enhanced nearly 18.6 times during anodal iontophoresis as compared to passive diffusion. For cathodal flux at pH 3.0 on similar iontophoretic treatment showed enhancement nearly 4 times.

A role of electrical inhibition in sensorimotor integration

Although it is accepted that extracellular fields generated by neuronal activity can influence the excitability of neighboring cells, whether this form of neurotransmission has a functional role remains open. In vivo field effects occur in the teleost Mauthner (M)-cell system, where a combination of structural features support the concept of inhibitory electrical synapses. A single spike in one M-cell evoked within as little as 2.2 ms of the onset of an abrupt sound, simulating a predatory strike, initiates a startle-escape behavior [Zottoli SJ (1977) J Exp Biol 66:243–254]. We show that such sounds produce synchronized action potentials in as many as 20 or more interneurons that mediate feed-forward electrical inhibition of the M-cell. The resulting action currents produce an electrical inhibition that coincides with the electrotonic excitatory drive to the M-cell; the amplitude of the peak of the inhibition is ≈40% of that of the excitation. When electrical inhibition is neutralized with an extracellular cathodal current pulse, subthreshold auditory stimuli are converted into ones that produce an M-spike. Because the timing of electrical inhibition is often the same as the latency of M-cell firing in freely swimming fish, we conclude that electrical inhibition participates in regulating the threshold of the acoustic startle-escape behavior. Therefore, a field effect is likely to be essential to the normal functioning of the neural network.

Cathodal current-induced vasodilation to single application and the amplified response to repeated application in humans rely on aspirin-sensitive mechanisms

Assumed to rely on an axon reflex, the current-induced vasodilation (CIV) interferes with the microvascular response to iontophoretic drug delivery. Mechanisms resulting in CIV are likely different at the anode and at the cathode. While studies have been conducted to understand anodal CIV, little information is available on cathodal CIV. The present study investigates CIV observed following 0.1-mA cathodal applications on forearms of healthy volunteers and the possible mechanisms involved. Results are expressed in percentage of the cutaneous heat-induced maximal vascular conductance [%MVC (means ± SE)]. 1) The amplitude of CIV was proportional to the duration of cathodal currents for periods of <1 min: r = 0.99. 2) Two current applications of 10 s, with 10-min interstimulation interval, induced a higher peak value of CIV (79.1 ± 8.6% MVC) than the one obtained with all-at-once 20-s current application (39.5 ± 4.3% MVC, P < 0.05). This amplified vascular response due to segmental application was observed for all tested interstimulation intervals (up to 40 min). 3) Two hours and 3 days following pretreatment with 1-g oral aspirin, the CIV observed following cathodal application, as well as the difference of cathodal CIV amplitude between all-at-once and segmented applications, were reduced. These findings suggest a role of prostaglandins, not only released from endothelial or smooth muscle cells, as direct vasodilator and/or as a sensitizer. Thus aspirin pretreatment could be used to decrease CIV resulting from all-at-once and repeated cathodal application and facilitate the study of the specific vascular effect induced by the drug delivered.

Effects of Red Nucleus Microstimulation on the Locomotor Pattern and Timing in the Intact Cat: A Comparison With the Motor Cortex

Effects of red nucleus microstimulation on the locomotor pattern and timing in the intact cat: a comparison with the motor cortex. To determine the extent to which the rubrospinal tract is capable of modifying locomotion in the intact cat, we applied microstimulation (cathodal current, 330 Hz; pulse duration 0.2 ms; maximal current, 25 μA) to the red nucleus during locomotion. The stimuli were applied either as short trains (33 ms) of impulses to determine the capacity of the rubrospinal tract to modify the level of electromyographic (EMG) activity in different flexors and extensors at different phases of the step cycle or as long trains (200 ms) of pulses to determine the effect of the red nucleus on cycle timing. Stimuli were also applied with the cat at rest (33-ms train). This latter stimulation evoked short-latency (average = 11.8–19.0 ms) facilitatory responses in all of the physiological flexor muscles of the forelimb that were recorded; facilitatory responses were also common in the elbow extensor, lateral head of triceps but were rare in the physiological wrist and digit extensor, palmaris longus. Responses were still evoked in most muscles when the current was decreased to near threshold (3–10 μA). Stimulation during locomotion with the short trains of stimuli evoked shorter-latency (average = 6.0–12.5 ms) facilitatory responses in flexor muscles during the swing phase of locomotion and, except in the case of the extensor digitorum communis, evoked substantially smaller responses in stance. The same stimuli also evoked facilitatory responses in the extensor muscles during swing and produced more complex effects involving both facilitation and suppression in stance. Increasing the duration of the train to 200 ms modified the amplitude and duration of the EMG activity of both flexors and extensors but had little significant effect on the cycle duration. In contrast, whereas stimulation of the motor cortex with short trains of stimuli during locomotion had very similar effects to that of the red nucleus, increasing the train duration to 200 ms frequently produced a marked reset of the step cycle by curtailing stance and initiating a new period of swing. The results suggest that whereas both the motor cortex and the red nucleus have access to the interneuronal circuits responsible for controlling the structure of the EMG activity in the step cycle, only the motor cortex has access to the circuits responsible for controlling cycle timing.

Generation and transit pathway of H+ is critical for inhibition of palmar sweating by iontophoresis in water

Passing galvanic current across the skin (known as "tap water iontophoresis" or TWI) inhibits sweating; however, its mechanism of action is unclear. Using improved methods, we confirmed that anodal current has more of an inhibitory effect than cathodal current, water is superior to saline, and the inhibitory effect is a function of the amperage used. To address the importance of current flowing through the pores, a layer of silicone grease was placed on the skin to reduce the shunt pathway across the epidermis. With silicone, total skin conductance decreased 60% without the sweat pores being occluded, swelling of the stratum corneum and collapse of the poral lumen was prevented, and current-induced inhibition of sweating was enhanced, most likely because of an increase in current density in the pores. The pH of anodal water, but not of saline, dropped to 3, whereas that of cathodal water increased to 10 during passage of current through the skin. Acidified anodal water was superior to alkaline water. Sweat glands isolated from TWI-induced anhidrotic palmar skin responded to methacholine in vitro, but the sweat rate and pharmacological sensitivity were slightly lowered. Thus the strong acidity generated by hydrolysis of water in the anodal bath and the further accumulation of H+ in the sweat duct by anodal current may be responsible for TWI-induced inhibition of sweating due to an unknown lesion(s) in the duct or sweat pore. The secretory coil function may also be altered because of exposure to intense acidity during TWI. The importance of H+ movement into the sweat pore for inhibition of sweating could be further exploited to develop new strategies for the control of sweating.