Illusory Directional Sensation Induced by Asymmetric Vibrations Influences Sense of Agency and Velocity in Wrist Motions.

Illusory directional sensations are generated through asymmetric vibrations applied to the fingertips and have been utilized to induce upper-limb motions in the rehabilitation and training of patients with visual impairment. However, its effects on motor control remain unclear. This study aimed to verify the effects of illusory directional sensations on wrist motion. We conducted objective and subjective evaluations of wrist motion during a motor task, while inducing an illusory directional sensation that was congruent or incongruent with wrist motion. We found that, when motion and illusory directional sensations were congruent, the sense of agency for motion decreased. This indicates an induction sensation of the hand being moved by the illusion. Interestingly, although no physical force was applied to the hand, the angular velocity of the wrist was higher in the congruent condition than that in the no-stimulation condition. The angular velocity of the wrist and electromyography signals of the agonist muscles were weakly positively correlated, suggesting that the participants may have increased their wrist velocity. In other words, the congruence between the direction of motion and illusory directional sensation induced the sensation of the hand being moved, even though the participants' wrist-motion velocity increased. This phenomenon can be explained by the discrepancy between the sensation of active motion predicted by the efferent copy, and that of actual motion caused by the addition of the illusion. The findings of this study can guide the design of novel rehabilitation methods.

Cyclo-glycylproline attenuates hydrogen peroxide-induced cellular damage mediated by the MDM2-p53 pathway in human neural stem cells.

Cyclo-glycylproline (cGP), a cyclic dipeptide containing a condensation bond between glycine and proline, is produced by the cyclization of the N-terminal tripeptide of insulin-like growth factor-1. Previous studies have shown that cGP administration exerts a neuroprotective effect and enhances the regenerative ability in rats with ischemic brain injury. The efficacy of cGP is medicated by regulating the bioavailability of insulin-like growth factor-1 (IGF-1), however, the molecular mechanisms underlying the neuroprotective effects of cGP on brain damage remains to be elucidated. In the current study, we investigated the cGP-mediated molecular mechanism in human fetal neural stem cells (hfNSCs) exposed to oxidative stress, which is a key factor affecting the development of several brain diseases, including traumatic brain injury and Parkinson's disease. We found that cGP treatment attenuated oxidative stress-induced cell death in cultured hfNSCs in a dose-dependent manner. Transcriptome analysis revealed that under oxidative stress conditions, p53-mediated signaling was activated, accompanied by upregulation of mouse double minute 2 homolog (MDM2), a p53-specific E3 ubiquitin ligase, in cGP-treated hfNSCs. By using a comprehensive protein phosphorylation array, we found that cGP induced the activation of Akt signaling pathway, which enhanced the expression of MDM2, in hfNSCs exposed to oxidative stress. Moreover, the MDM2 inhibitor nutlin-3 inhibited the protective effect of cGP on oxidative stress-induced cell death and apoptosis. Therefore, cGP attenuates oxidative stress-induced cell death mediated by the interplay between IGF-1 signaling and the MDM2-p53 pathway in human NSCs. We revealed the molecular mechanism underlying cGP-induced neuroprotective properties in a model of brain damage.

Oral administration of cyclic glycyl-proline facilitates task learning in a rat stroke model.

Cyclic glycyl-proline (cGP) exerts neuroprotective effects against ischemic stroke and may promote neural plasticity or network remodeling. We sought to determine to what extent oral administration of cGP could facilitate task learning in rats with ischemic lesions. We trained rats to perform a choice reaction time task using their forepaws. One week after changing the food to pellets containing cGP (no cGP: 0 mg/kg; low cGP: 25 mg/kg; and high cGP: 75 mg/kg), we made a focal ischemic lesion on the left or right forepaw area of the sensorimotor cortex. After recovery of task performance, we altered the correct-response side of the task, and then analyzed the number of training days required for the rat to reach a learning criterion (error rate < 15%) and the regulation of adult neurogenesis in the subventricular zones (SVZs), taking lesion size into account. The low-cGP group required fewer training days for task learning than the no-cGP group. Unexpectedly, rats with larger lesions required fewer training days in the no-cGP and low-cGP groups, but more training days in the high-cGP group. The number of Ki67-immunopositive cells (indicating proliferative cells) in ipsilesional SVZ increased more rapidly in the low-cGP and high-cGP groups than in the no-cGP group. However, lesion size had only a small effect on required training days and the number of Ki67-immunopositive cells. We conclude that oral administration of cGP can facilitate task learning in rats with focal ischemic infarction through neural plasticity and network remodeling, even with minimal neuroprotective effects.

A pseudo-mastication sound presentation device to improve the texture of nursing care foods.

The texture of foods is affected by concurrent auditory sensations. To improve the texture of nursing care foods, we developed a pseudo-mastication sound presentation device based on electromyogram (EMG) signals from the muscles of mastication. EMG signals have enabled us to promptly present care recipients with pseudo-mastication sounds. However, actual mastication sounds vary in intensity and duration more than EMG signals. Here, we investigated changes in EMG signals and actual mastication sounds during the mastication of two food types (rice crackers and Japanese pickles) to improve our device. We found that the intensity and duration of mastication sounds decreased as the number of mastication strokes increased. Furthermore, the intensity and duration of mastication sounds and the latency between the onset of EMG signals and the onset of mastication sounds also varied by food type. For EMG signals, only the intensity varied by food type. Based on our findings, we modified our pseudo-mastication sound presentation device to enable control of the intensity and duration of pseudo-mastication sounds based on the number of mastication strokes and food type. Reproducing more natural pseudo-mastication sounds can improve care recipients' motivation for ingesting nursing care foods, thus preventing malnutrition and frailty.

Effects of forced movements on learning: Findings from a choice reaction time task in rats.

To investigate how motor sensation facilitates learning, we used a sensory-motor association task to determine whether the sensation induced by forced movements contributes to performance improvements in rats. The rats were trained to respond to a tactile stimulus (an air puff) by releasing a lever pressed by the stimulated (compatible condition) or nonstimulated (incompatible condition) forepaw. When error rates fell below 15%, the compatibility condition was changed (reversal learning). An error trial was followed by a lever activation trial in which a lever on the correct or the incorrect response side was automatically elevated at a preset time of 120, 220, 320, or 420 ms after tactile stimulation. This lever activation induced forepaw movement similar to that in a voluntary lever release response, and also induced body movement that occasionally caused elevation of the other forepaw. The effects of lever activation may have produced a sensation similar to that of voluntary lever release by the forepaw on the nonactivated lever. We found that the performance improvement rate was increased by the lever activation procedure on the incorrect response side (i.e., with the nonactivated lever on the correct response side). Furthermore, the performance improvement rate changed depending on the timing of lever activation: Facilitative effects were largest with lever activation on the incorrect response side at 320 ms after tactile stimulation, whereas hindering effects were largest for lever activation on the correct response side at 220 ms after tactile stimulation. These findings suggest that forced movements, which provide tactile and proprioceptive stimulation, affect sensory-motor associative learning in a time-dependent manner.

In vivo neuronal action potential recordings via three-dimensional microscale needle-electrode arrays.

Very fine needle-electrode arrays potentially offer both low invasiveness and high spatial resolution of electrophysiological neuronal recordings in vivo. Herein we report the penetrating and recording capabilities of silicon-growth-based three-dimensional microscale-diameter needle-electrodes arrays. The fabricated needles exhibit a circular-cone shape with a 3-µm-diameter tip and a 210-µm length. Due to the microscale diameter, our silicon needles are more flexible than other microfabricated silicon needles with larger diameters. Coating the microscale-needle-tip with platinum black results in an impedance of ~600 kΩ in saline with output/input signal amplitude ratios of more than 90% at 40 Hz-10 kHz. The needles can penetrate into the whisker barrel area of a rat's cerebral cortex, and the action potentials recorded from some neurons exhibit peak-to-peak amplitudes of ~300 µVpp. These results demonstrate the feasibility of in vivo neuronal action potential recordings with a microscale needle-electrode array fabricated using silicon growth technology.

Organization of local horizontal functional interactions between neurons in the inferior temporal cortex of macaque monkeys.

Detailed knowledge of neuronal circuitry is necessary for understanding the mechanisms underlying information processing in the brain. We investigated the organization of horizontal functional interactions in the inferior temporal cortex of macaque monkeys, which plays important roles in visual object recognition. Neuronal activity was recorded from the inferior temporal cortex using an array of eight tetrodes, with spatial separation between paired neurons up to 1.4 mm. We evaluated functional interactions on a time scale of milliseconds using cross-correlation analysis of neuronal activity of the paired neurons. Visual response properties of neurons were evaluated using responses to a set of 100 visual stimuli. Adjacent neuron pairs tended to show strong functional interactions compared with more distant neuron pairs, and neurons with similar stimulus preferences tended to show stronger functional interactions than neurons with different stimulus preferences. Thus horizontal functional interactions in the inferior temporal cortex appear to be organized according to both cortical distances and similarity in stimulus preference between neurons. Furthermore, the relationship between strength of functional interactions and similarity in stimulus preference observed in distant neuron pairs was more prominent than in adjacent pairs. The results suggest that functional circuitry is specifically organized, depending on the horizontal distances between neurons. Such specificity endows each circuit with unique functions.

Enlarged gold-tipped silicon microprobe arrays and signal compensation for multi-site electroretinogram recordings in the isolated carp retina.

In order to record multi-site electroretinogram (ERG) responses in isolated carp retinae, we utilized three-dimensional (3D), extracellular, 3.5-µm-diameter silicon (Si) probe arrays fabricated by the selective vapor-liquid-solid (VLS) growth method. Neural recordings with the Si microprobe exhibit low signal-to-noise (S/N) ratios of recorded responses due to the high-electrical-impedance characteristics of the small recording area at the probe tip. To increase the S/N ratio, we designed and fabricated enlarged gold (Au) tipped Si microprobes (10-µm-diameter Au tip and 3.5-µm-diameter probe body). In addition, we demonstrated that the signal attenuation and phase delay of ERG responses recorded via the Si probe can be compensated by the inverse filtering method. We conclude that the reduction of probe impedance and the compensation of recorded signals are useful approaches to obtain distortion-free recording of neural signals with high-impedance microelectrodes.

Multineuronal vectorization is more efficient than time-segmental vectorization for information extraction from neuronal activities in the inferior temporal cortex.

In order for patients with disabilities to control assistive devices with their own neural activity, multineuronal spike trains must be efficiently decoded because only limited computational resources can be used to generate prosthetic control signals in portable real-time applications. In this study, we compare the abilities of two vectorizing procedures (multineuronal and time-segmental) to extract information from spike trains during the same total neuron-seconds. In the multineuronal vectorizing procedure, we defined a response vector whose components represented the spike counts of one to five neurons. In the time-segmental vectorizing procedure, a response vector consisted of components representing a neuron's spike counts for one to five time-segment(s) of a response period of 1 s. Spike trains were recorded from neurons in the inferior temporal cortex of monkeys presented with visual stimuli. We examined whether the amount of information of the visual stimuli carried by these neurons differed between the two vectorizing procedures. The amount of information calculated with the multineuronal vectorizing procedure, but not the time-segmental vectorizing procedure, significantly increased with the dimensions of the response vector. We conclude that the multineuronal vectorizing procedure is superior to the time-segmental vectorizing procedure in efficiently extracting information from neuronal signals.

Epileptiform discharges and neuronal plasticity in the acute peri-infarct cortex of rats.

While the peri-infarct cortex is thought to be responsible for functional recovery, the site is also a strong candidate for post-stroke seizures. Since it is crucial to identify the conditions when the site is changed with such beneficial or detrimental results, the peri-infarct changes were investigated before and just after inducing a focal infarct on rat cortex. The receptive fields in the peri-infarct cortex began to increase a few hours after the infarct, and reached a statistical significance at 6 hours (Dunnett post hoc tests; p<0.05). In temporal association with these changes, EEG in the peri-infarct cortex showed epileptiform activities containing large-amplitude spike-and-wave discharges. The gross amplitude, peak-to-peak amplitude and burst frequency showed statistically significant increases within 4 hours, in comparison to those of the controls (Dunnett post hoc tests; p<0.05). FFT power spectrum analyses showed a distinct increase in approximately 25 Hz frequency bands in the post-stroke groups. The homogeneous area of the contralateral hemisphere in the infarct group, in contrast, did not show such plastic or excitability changes. This study demonstrated, for the first time, that the peri-infarct cortex acquires the characteristics of potential epileptogenesis and functional recovery within hours of a stroke.

Microtube-based electrode arrays for low invasive extracellular recording with a high signal-to-noise ratio.

We report on the development of a microtube electrode array as a neural interface device. To combine the desired properties for the neural interface device, such as low invasiveness with a small needle and a good signal-to-noise ratio in neural recordings, we applied the structure of a glass pipette electrode to each microtube electrode. The device was fabricated as sub-5-microm-diameter out-of-plane silicon dioxide microtube arrays using silicon microneedle templates, which are grown by the selective vapor-liquid-solid method. The microtubes had inner diameters of 1.9-6.4 microm and a length of 25 microm. Impedances ranged from 220 kOmega to 1.55 MOmega, which are less than those for conventional microneedles. In addition, the microtube electrodes had less signal attenuation than conventional microneedle electrodes. We confirmed that the effects of parasitic capacitances between neighboring microtubes and channels were sufficiently small using a test signal. Finally, neural responses evoked from a rat peripheral nerve were recorded in vivo using a microtube electrode to confirm that this type of electrode can be used for both electrophysiological measurements and as a neural interface device.

Out-of-plane microtube arrays for drug delivery--liquid flow properties and an application to the nerve block test.

We have proposed fabricating very fine out-of-plane silicon-dioxide microtube arrays using a selective vapor-liquid-solid (VLS) growth technique and microfabrication processes. In this study, we elucidated the liquid-flow properties of microtubes with different inner diameters. Our fabricated microtubes were 0.5 microm in wall thickness; 20 microm in height; and either 2.5 microm, 4.1 microm, 4.6 microm, or 6.4 microm in inner diameter. We determined the relationship between the flow pressure and the liquid flow rate through the microtube. We also conducted a nerve block test, in which a microtube with 4.6 microm inner diameter was used to administer lidocaine solution (Na channel blocker) to the rat sciatic nerve. This successful test represents the first reported use of a microtube for drug delivery to the peripheral nerve of a rat. We conclude that the proposed microtube array and its fabrication process might contribute to developing pharmacological devices.

Tracking spike-amplitude changes to improve the quality of multineuronal data analysis.

During extracellular electrophysiological recording experiments, the waveform of neuronal spikes recorded from a single neuron often changes. These spike-waveform changes make single-neuron identification difficult, particularly when the activities of multiple neurons are simultaneously recorded with a multichannel microelectrode, such as a tetrode or a heptode. We have developed a tracking method of individual neurons despite their changing spike amplitudes. The method is based on a bottom-up hierarchical clustering algorithm that tracks each neuron's spike cluster during temporally overlapping clustering periods. We evaluated this method by comparing spike sorting with and without cluster tracking of an identical series of multineuronal spikes recorded from monkey area-TE neurons responding to a set of visual stimuli. According to Shannon's information theory, errors in spike-amplitude tracking reduce the expected value of the amount of information about a stimulus set that is transferred by the spike train of a cluster. In this study, cluster tracking significantly increased the expected value of the amount of information transferred by a spike train (p < 0.01). Additionally, the stability of the stimulus preference and that of the cross-correlation between clusters improved significantly (p < 0.000001). We conclude that cluster tracking improves the quality of multineuronal data analysis.

Involvement of the histaminergic system in renal sympathetic and cardiovascular responses to leptin and ghrelin.

Previous studies have demonstrated that histamine affects blood pressure (BP) in anesthetized rats. Here, we examined the effects of lateral cerebral ventricular (LCV) injection of various doses of histamine on renal sympathetic nerve activity (RSNA) and BP in anesthetized rats. LCV injection of a low dose of histamine (0.0001nmol) suppressed RSNA and BP. Conversely, a high dose of histamine (100nmol) elevated both RSNA and BP. Moreover, inhibiting effects of a low dose of histamine were eliminated by LCV pre-injection of thioperamide, an antagonist of histaminergic H3-receptor, and accelerating effects of a high dose of histamine were abolished by LCV pre-injection of diphenhydramine, an antagonist of histaminergic H1-receptor. Thus, these evidences suggest that central histamine affects RSNA and BP via histaminergic receptors. In addition, we examined a role for histaminergic system in cardiovascular modulators such as leptin and ghrelin. The LCV pre-injection of thioperamide clearly blocked suppressing effects of ghrelin on RSNA and BP. The LCV pre-injection of diphenhydramine also blocked elevating effects of leptin. Therefore, these results suggest that leptin and ghrelin might affect RSNA and BP by mediating central histaminegic H1- and H3-receptors, respectively.

A choice reaction-time task in the rat: a new model using air-puff stimuli and lever-release responses.

We have developed a two-lever choice reaction-time (RT) task to investigate the behavioral and neural mechanisms of stimulus-response compatibility in rats. In the task, the rat pressed two levers with its forepaws during the preparation period of each trial, and then quickly responded to an air-puff stimulus on its left or right forepaw by releasing the lever on the same side (compatible condition) or the opposite side (incompatible condition) of the stimulus. Twenty rats successfully learned the task in both the compatible and incompatible conditions. Two stimulus-response compatibility effects were observed: the RT was shorter and the error rate was lower in the compatible condition than in the incompatible condition. The trial sequence also affected the results and a speed-accuracy tradeoff was observed. These results are consistent with those reported for human RT tasks. Furthermore, a lesion in the forepaw-sensorimotor cortex caused increases in the RTs for stimulus detection and/or response movement with the contralateral forepaw, suggesting that the task was mediated by this brain area. We conclude that this instrumental task for rats can be regarded as a model for human RT tasks and can be used to investigate the neural basis of the compatibility effects.

Quantitative analysis of functional clustering of neurons in the macaque inferior temporal cortex.

Neurons with similar preferences for two-dimensional shapes of intermediate complexity cluster in area TE of the monkey inferior temporal cortex. To further characterize the functional structure of area TE, we quantitatively analyzed various aspects of the visual responses of closely located neurons by applying multiple single-unit recording techniques in anesthetized monkeys. Examination of the visual responses elicited with a large, predetermined set of visual stimuli confirmed previous findings that nearby neurons, on average, exhibited positively correlated preferences for a set of visual stimuli. Nearby neurons also tended to be similar in their receptive-field organization and contrast-polarity preference. In contrast, no correlation was found in the size tuning of neighboring neurons. Pooling or subtraction of activities between a pair of nearby neurons was shown to improve stimulus discriminability, if the neuron pair had positively or negatively correlated stimulus preferences, respectively. These results indicate that nearby TE neurons share some aspects of stimulus preference, but their response selectivity differ in other aspects. Both pooling and subtraction between nearby neurons can reduce across-trial response variability, if these decoding strategies are applied to appropriate neuronal pools.

Hyperexcitability-associated rapid plasticity after a focal cerebral ischemia.

BACKGROUND AND PURPOSE: This article addresses how neuroplastic changes are initiated after an ischemic stroke. METHODS: A focal cerebral ischemia was photochemically induced on the primary somatosensory cortex of rats, and in vivo electrophysiological recordings were performed on the peri-infarct cortex before and from 1 to 6 hours after the infarction. RESULTS: Paired-pulse analysis of evoked field potentials to peripheral electrical stimuli showed statistically significant neuronal hyperexcitability that was associated with rapid expansion of receptive fields (146.1% at 1 hour and 553.6% at 6 hours) as early as 1 hour after the infarction (P<0.05). Current source density analysis revealed increased current sinks in cortical layer II/III. CONCLUSIONS: Our electrophysiological results showed, for the first time to our knowledge, rapid plastic changes in the peri-infarct cortex during the hyperacute stage of an ischemic stroke. Manipulation of this rapid plasticity may affect subsequent plastic changes.

Presumed inhibitory neurons in the macaque inferior temporal cortex: visual response properties and functional interactions with adjacent neurons.

Neurons in area TE of the monkey inferior temporal cortex respond selectively to images of particular objects or their characteristic visual features. The mechanism of generation of the stimulus selectivity, however, is largely unknown. This study addresses the role of inhibitory TE neurons in this process by examining their visual response properties and interactions with adjacent target neurons. We applied cross-correlation analysis to spike trains simultaneously recorded from pairs of adjacent neurons in anesthetized macaques. Neurons whose activity preceded a decrease in activity from their partner were presumed to be inhibitory neurons. Excitatory neurons were also identified as the source neuron of excitatory linkage as evidenced by a sharp peak displaced from the 0-ms bin in cross-correlograms. Most inhibitory neurons responded to a variety of visual stimuli in our stimulus set, which consisted of several dozen geometrical figures and photographs of objects, with a clear stimulus preference. On average, 10% of the stimuli increased firing rates of the inhibitory neurons. Both excitatory and inhibitory neurons exhibited a similar degree of stimulus selectivity. Although inhibitory neurons occasionally shared the most preferred stimuli with their target neurons, overall stimulus preferences were less similar between adjacent neurons with inhibitory linkages than adjacent neurons with common inputs and/or excitatory linkages. These results suggest that inhibitory neurons in area TE are activated selectively and exert stimulus-specific inhibition on adjacent neurons, contributing to shaping of stimulus selectivity of TE neurons.

Activation of the renal sympathetic nerve by leptin microinjection into the ventromedial hypothalamus in rats.

Leptin produced in white adipose tissue activates sympathetic nerve activity via the ventromedial hypothalamus (VMH) within the central nervous system (CNS). Using an electrophysiological technique, we investigated whether direct microinjection of leptin into the VMH elevates renal sympathetic nerve activity (RSNA) and blood pressure (BP) in anesthetized rats. Microinjection of leptin (100 ng/microL) into the VMH caused significant activation of RSNA from 25 minutes after administration but no affect on BP. We concluded that leptin-induced elevation of RSNA is mediated via the VMH or its vicinity within the CNS.

Sensitization of glutamate release and N-methyl-D-aspartate receptor response by transient dopamine pretreatment in prefrontal cortex of rats.

We studied biochemically the effect of transient dopamine pretreatment on the regulation of glutamate transmission in medial prefrontal cortex of rats in vivo and in vitro. Aversive stimuli transiently increased the glutamate concentration and its repetition reduced the response in the medial prefrontal microdialysate of freely moving rats. The rate of habituation obeyed linear regression. The medial prefrontal intracellular calcium response to repetitive N-methyl-D-aspartate perfusion showed linearly regressive desensitization in fluorescence videomicroscopy of the fura-2 stained slice in vitro. Transient dopamine treatment 10-20 min prior to repetition restored both decreased responses in a linearly regressive manner, also indicating that their decrease was not due to fatigue. These findings suggest that the effect of transient dopamine pretreatment continues redundantly to sensitize/resensitize subsequent pre- and postsynaptic prefrontal glutamate transmission in an orderly manner.