P/Q type (Cav2.1) Calcium Channel Blocker ω-Agatoxin IVA Alters Cleaved Caspase-3 and BDNF Expressions in the Rat Brain and Suppresses Seizure Activity.

High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis. Peripheral nerve injuries often result in long-lasting functional deficits, prompting the need for effective interventions. MitoTEMPO (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride) is a mitochondria-targeted antioxidant that has shown protective and therapeutic effects against pathologies associated with reactive oxygen species. This study explores the utilization of MitoTEMPO as a therapeutic and protective agent for sciatic nerve crush injuries. By employing advanced mathematical approaches, the study seeks to comprehensively analyze nerve conduction parameters, nerve excitability, and the distribution of nerve conduction velocities to gauge the potential. Forty Wistar-Albino rats were randomly divided into following groups: (I) SHAM-animals subjected to sham operation and treated intraperitoneally (i.p.) with vehicle (bidistilled water) for 14 days; (II) CI (crush injury)-animals subjected to CI and treated with vehicle 14 days; (III) MiP-animals subjected to 7 days i.p. MitoTEMPO treatment before CI (0.7 mg/kg/day dissolved in vehicle) and, only vehicle for 7 days after CI, protective MitoTEMPO; and (IV) MiT-animals i.p. treated with only vehicle for 7 days before CI and 7 days with MitoTEMPO (0.7 mg/kg/day dissolved in vehicle) after CI, therapeutic MitoTEMPO. Nerve excitability parameters were measured, including rheobase and chronaxie, along with compound action potential (CAP) recordings. Advanced mathematical analyses were applied to CAP recordings to determine nerve conduction velocities and distribution patterns. The study revealed significant differences in nerve excitability parameters between groups. Nerve conduction velocity was notably reduced in the MiP and CI groups, whereas CAP area values were diminished in the MiP and CI groups compared to the MiT group. Furthermore, CAP velocity was lower in the MiP and CI groups, and maximum depolarization values were markedly lower in the MiP and CI groups compared to the SHAM group. The distribution of nerve conduction velocities indicated alterations in the composition of nerve fiber groups following crush injuries. In conclusion, postoperative MitoTEMPO administration demonstrated promising results in mitigating the detrimental effects of nerve crush injuries.

Auditory cortical responses to abrupt lateralization shifts do not reflect the activity of hemifield-specific units involved in opponent coding of auditory space.

Recent studies show that the classical model based on axonal delay-lines may not explain interaural time difference (ITD) based spatial coding in humans. Instead, a population-code model called "opponent channels model" (OCM) has been suggested. This model comprises two competing channels respectively for the two auditory hemifields, each with a sigmoidal tuning curve. Event-related potentials (ERPs) to ITD-changes are used in some studies to test the predictions of this model by considering the sounds before and after the change as adaptor and probe stimuli, respectively. It is assumed in these studies that the former stimulus causes adaptation of the neurons selective to its side, and that the ERP N1-P2 response to the ITD-change is the specific response of the neurons with selectivity to the side of probe sound. However, these ERP components are known as a global, non-specific acoustic change complex of cortical origin evoked by any change in the auditory environment. It probably does not genuinely reflect the activity of some stimulus-specific neuronal units that have escaped the refractory effect of the preceding adaptor, which means a violation of the crucial assumption in an adaptor-probe paradigm. To assess this viewpoint, we conducted two experiments. In the first one, we recorded ERPs to abrupt lateralization shifts of click trains having various pre- and post-shift ITDs within the physiological range of -600µs to +600µs. Magnitudes of the ERP components P1, N1, and P2 to these ITD-shifts did not comply with the additive behavior of partial probe responses presumed for an adaptor-probe paradigm, casting doubt on the accuracy of testing sensory coding models by using ERPs to abrupt lateralization changes. Findings of the second experiment, involving ERPs to conjoint outwards/transverse shift stimuli also supported this conclusion.

Musical mirror-symmetrical movement tasks: comparison of rhythm versus melody-playing.

Bimanual mirror-symmetrical movement (MSM) is relatively easy to control movement. Different MSM tasks may have different activations and interhemispheric interactions. The purpose of this study is to compare anatomo-physiological features such as hemispheric activations and dominance of two different MSMs, namely melody-playing and rhythm. We examined functional MRI (fMRI) recordings in a group of fifteen right-handed pianists performing two separate tasks: bimanual rhythm and bimanual melody-playing on two different keyboards with standard key order for right hand and reversed for left hand, which allows homolog fingers' movements. Activations and laterality indices on fMRI were examined. The results show that significant cerebellar activations (especially in anterior cerebellum) in both groups. Significant primary sensorimotor cortical activations are observed in the melody-playing group. While there are also bilaterally symmetric activations, and laterality indices suggest overall lateralization towards the left hemisphere in both groups. Activations in the left fronto-parietal cortex, left putamen and left thalamus in conjunction with right cerebellar activations suggest that the left cortico-thalamo-cerebellar loop may be a dominant loop. Dynamic causal modeling (DCM) indicates the presence of causal influences from the left to the right cerebral cortex. In conclusion, melody-playing with bimanual MSM is a complex in-phase task and may help activate the bilateral cortical areas, and left hemisphere is dominant according to laterality indices and DCM results. On the other hand, bimanual rhythm is a simpler in-phase task and may help activate subcortical areas, which might be independent of the voluntary cortical task.

Axonal excitability and conduction alterations caused by levobupivacaine in rat.

In this study, effects of the long-acting amide-type local anesthetic levobupivacaine on axonal conduction and excitability parameters of the rat sciatic nerve were thoroughly examined both in vitro and in vivo. In order to deduce its effects on isolated nerve conduction, compound nerve action potential (CNAP) recordings were performed using the suction method over sciatic nerves of Wistar rats before and after administration of 0.05 % (1.7 mmol L-1) levobupivacaine. Levobupivacaine caused complete CNAP area and amplitude depression by blocking conduction in a time-dependent manner. To assess the influence of levobupivacaine on in vivo excitability properties, threshold-tracking (TT) protocols were performed at sciatic nerves of rats injected with perineural 0.05 % (1.7 mmol L-1) levobupivacaine or vehicle alone. Charge-duration TT results revealed that levobupivacaine increases the rheobase and decreases the strength-duration time constant, suggesting interference of the anesthetic with the opening of Na+ channels. Twenty and 40 % threshold electrotonus curves were found for both groups to follow the same paths, suggesting no significant effect of levobupivacaine on K+ channels for either the fastest or relatively slow conducting fibers. Current-threshold relationship results revealed no significant effect on axonal rectifying channels. However, according to the results of the recovery cycle protocol yielding the pattern of excitability changes following the impulse, potential deviation was found in the recovery characteristics of Na+ channels from the absolute refractory period. Consequently, conduction blockage caused by levobupivacaine may not be due to the passive (capacitive) properties of axon or the conductance of potassium channels but to the decrease in sodium channel conductance.

The Triple-Flash Illusion Reveals a Driving Role of Alpha-Band Reverberations in Visual Perception.

The modulatory role of spontaneous brain oscillations on perception of threshold-level stimuli is well established. Here, we provide evidence that alpha-band (∼10 Hz) oscillations not only modulate perception of threshold-level sensory inputs but also can drive perception and generate percepts without a physical stimulus being present. We used the "triple-flash" illusion: Occasional perception of three flashes when only two spatially coincident veridical ones, separated by ∼100 ms, are presented. The illusion was proposed to result from superposition of two hypothetical oscillatory impulse response functions generated in response to each flash: When the delay between flashes matches the period of the oscillation, the superposition enhances a later part of the oscillation that is normally damped; when this enhancement crosses perceptual threshold, a third flash is erroneously perceived (Bowen, 1989). In Experiment 1, we varied stimulus onset asynchrony and validated Bowen's theory: The optimal stimulus onset asynchrony for illusion to occur was correlated, across human subjects (both genders), with the subject-specific impulse response function period determined from a separate EEG experiment. Experiment 2 revealed that prestimulus parietal, but no occipital, alpha EEG phase and power, as well as poststimulus alpha phase-locking, together determine the occurrence of the illusion on a trial-by-trial basis. Thus, oscillatory reverberations create something out of nothing: A third flash where there are only two.SIGNIFICANCE STATEMENT We highlight a novel property of alpha-band (∼10 Hz) oscillations based on three experiments (two EEG and one psychophysics) by demonstrating that alpha-band oscillations do not merely modulate perception, but can also drive perception. We show that human participants report seeing a third flash when only two are presented (the "triple-flash" illusion) most often when the interflash delay matches the period of participant's oscillatory impulse response function reverberating in alpha. Within-subject, the phase and power of ongoing parietal, but not occipital, alpha-band oscillations at the time of the first flash determine illusory percept on a trial-by-trial basis. We revealed a physiologically plausible mechanism that validates and extends the original theoretical account of the triple-flash illusion proposed by Bowen in 1989.

On the cyclic nature of perception in vision versus audition.

Does our perceptual awareness consist of a continuous stream, or a discrete sequence of perceptual cycles, possibly associated with the rhythmic structure of brain activity? This has been a long-standing question in neuroscience. We review recent psychophysical and electrophysiological studies indicating that part of our visual awareness proceeds in approximately 7-13 Hz cycles rather than continuously. On the other hand, experimental attempts at applying similar tools to demonstrate the discreteness of auditory awareness have been largely unsuccessful. We argue and demonstrate experimentally that visual and auditory perception are not equally affected by temporal subsampling of their respective input streams: video sequences remain intelligible at sampling rates of two to three frames per second, whereas audio inputs lose their fine temporal structure, and thus all significance, below 20-30 samples per second. This does not mean, however, that our auditory perception must proceed continuously. Instead, we propose that audition could still involve perceptual cycles, but the periodic sampling should happen only after the stage of auditory feature extraction. In addition, although visual perceptual cycles can follow one another at a spontaneous pace largely independent of the visual input, auditory cycles may need to sample the input stream more flexibly, by adapting to the temporal structure of the auditory inputs.

No counterpart of visual perceptual echoes in the auditory system.

It has been previously demonstrated by our group that a visual stimulus made of dynamically changing luminance evokes an echo or reverberation at ~10 Hz, lasting up to a second. In this study we aimed to reveal whether similar echoes also exist in the auditory modality. A dynamically changing auditory stimulus equivalent to the visual stimulus was designed and employed in two separate series of experiments, and the presence of reverberations was analyzed based on reverse correlations between stimulus sequences and EEG epochs. The first experiment directly compared visual and auditory stimuli: while previous findings of ~10 Hz visual echoes were verified, no similar echo was found in the auditory modality regardless of frequency. In the second experiment, we tested if auditory sequences would influence the visual echoes when they were congruent or incongruent with the visual sequences. However, the results in that case similarly did not reveal any auditory echoes, nor any change in the characteristics of visual echoes as a function of audio-visual congruence. The negative findings from these experiments suggest that brain oscillations do not equivalently affect early sensory processes in the visual and auditory modalities, and that alpha (8-13 Hz) oscillations play a special role in vision.

Lateralisation of sound in temporal-lobe epilepsy: comparison between pre- and postoperative performances and ERPs.

OBJECTIVE: Our aim was to investigate if spatial hearing is impaired in mesial temporal lobe epilepsy and temporal lobectomy has an effect on this function. METHODS: Thirteen patients with mesial temporal lobe epilepsy (TLE) due to sclerosis in their left (n=6) or right (n=7) hippocampus were studied. Their sound lateralisation performance indexed by d' was tested against that of a group of normal subjects (n=13). Patients' ERPs to lateralisation shifts induced by interaural disparities of intensity (IID) and time (ITD) were also recorded. Eight of the patients were re-tested after they underwent anterior temporal lobectomy, which involved the resection/removal of medial structures including amygdala, hippocampus and parahippocampal gyrus. RESULTS: The sound-lateralisation performance of the TLE patients was significantly lower than normal subjects, and this disadvantage of the patients was specific to IID-based lateralisation. Amplitudes of their N1 and P2 responses to laterally shifting sounds were much lower than those reported previously for normal subjects. Lobectomy did not have a statistically significant effect on patients' sound-lateralisation performance nor on the amplitude of their auditory directional ERPs. CONCLUSIONS: The results show that especially the IID-based sound-lateralisation performance is impaired in TLE patients and that lobectomy should not cause any further deterioration. SIGNIFICANCE: This study suggests that a test for assessing the ability of sound lateralisation based on each of the IID and ITD cues should be included in the evaluation of TLE patients.

Somatosensory conduction velocity distribution of median nerve middle palmar digital component.

Collision technique is one of the methods used to obtain the relative number of fibers in a nerve bundle. In 25 normal subjects, the right median nerve has been concurrently stimulated at proximal (elbow) and distal (wrist) locations, and the resultant compound action potentials (CAP) were recorded at the middle finger via ring electrodes. The delay between the two stimuli (Inter Stimulus Interval; ISI), beginning from 7 ms, has been decreased in 0.1 ms steps, until the CAPs, elicited by proximal stimulation, totally disappeared. The obtained data have been transferred to computer medium for further analysis. In this procedure, areas under proximal CAPs have been obtained for each ISI value. Using these areas, the relative numbers of fibers (%) belonging to the middle proper palmar digital (MPPD) component of sensory median nerve have been derived. The mean conduction velocities in MPPD component of sensory median nerve ranged from 40 m/s to 68 m/s. In the histogram, a large amount of heaping of the relative number of fibers has been observed in 48-59 m/s conduction velocity interval with the ratio of 64%, although there has been a 21% group having 43-47 ms conduction velocity. These results can be a guide to future studies concerning basic and clinical nerve conduction studies.

The effect of bupivacaine on compound action potential parameters of sciatic nerve fibers.

The aim of this study was to document the effects of the local anesthetic agent bupivacaine on individual fibers of peripheral nerve. To accomplish this objective, compound action potentials (CAPs) were recorded from isolated frog sciatic nerves treated with bupivacaine for seven individual concentration levels. Numerical and fast Fourier transform (FFT) analysis were performed on these recordings. The areas, latency periods, maximum and minimum derivatives, and power spectrums of the CAPs were computed. The results show that the area and the absolute values of maximum and minimum derivatives decrease linearly as bupivacaine concentration increases. The power spectrum of the CAPs, which resides in the 0-1000 Hz interval, initially shifts to higher frequencies then returns to lower frequency region again with increasing bupivacaine concentration. Due to this result, it is thought that bupivacaine inhibits nerve fibers in a dose-dependent manner. It primarily affects the fibers having the least myelin sheets (motor fibers), then it begins to depress the fast conducting (neurosensorial) fibers as the bupivacaine concentration increases, and finally blocks the unmyelinated C-fibers.