Neuronal Encoding of Self and Others' Head Rotation in the Macaque Dorsal Prefrontal Cortex.

Following gaze is a crucial skill, in primates, for understanding where and at what others are looking, and often requires head rotation. The neural basis underlying head rotation are deemed to overlap with the parieto-frontal attention/gaze-shift network. Here, we show that a set of neurons in monkey's Brodmann area 9/46dr (BA 9/46dr), which is involved in orienting processes and joint attention, becomes active during self head rotation and that the activity of these neurons cannot be accounted for by saccade-related activity (head-rotation neurons). Another set of BA 9/46dr neurons encodes head rotation performed by an observed agent facing the monkey (visually triggered neurons). Among these latter neurons, almost half exhibit the intriguing property of encoding both execution and observation of head rotation (mirror-like neurons). Finally, by means of neuronal tracing techniques, we showed that BA 9/46dr takes part into two distinct networks: a dorso/mesial network, playing a role in spatial head/gaze orientation, and a ventrolateral network, likely involved in processing social stimuli and mirroring others' head. The overall results of this study provide a new, comprehensive picture of the role of BA 9/46dr in encoding self and others' head rotation, likely playing a role in head-following behaviors.

Orienting movements in area 9 identified by long-train ICMS.

The effect of intracortical microstimulation has been studied in several cortical areas from motor to sensory areas. The frontal pole has received particular attention, and several microstimulation studies have been conducted in the frontal eye field, supplementary eye field, and the premotor ear-eye field, but no microstimulation studies concerning area 9 are currently available in the literature. In the present study, to fill up this gap, electrical microstimulation was applied to area 9 in two macaque monkeys using long-train pulses of 500-700-800 and 1,000 ms, during two different experimental conditions: a spontaneous condition, while the animals were not actively fixating on a visual target, and during a visual fixation task. In these experiments, we identified backward ear movements, goal-directed eye movements, and the development of head forces. Kinematic parameters for ear and eye movements overlapped in the spontaneous condition, but they were different during the visual fixation task. In this condition, ear and eye kinematics have an opposite behavior: movement amplitude, duration, and maximal and mean velocities increase during a visual fixation task for the ear, while they decrease for the eye. Therefore, a top-down visual attention engagement could modify the kinematic parameters for these two effectors. Stimulation with the longest train durations, i.e., 800/1,000 ms, evokes not only the highest eye amplitude, but also a significant development of head forces. In this research article, we propose a new vision of the frontal oculomotor fields, speculating a role for area 9 in the control of goal-directed orienting behaviors and gaze shift control.

Recovery of damaged skeletal muscle in mdx mice through low-intensity endurance exercise.

The lack of dystrophin in mdx mice leads to cycles of muscle degeneration and regeneration processes. Various strategies have been proposed in order to reduce the muscle-wasting component of muscular dystrophy, including implementation of an exercise programme. The aim of this study was to examine how low-intensity endurance exercise affects the degeneration-regeneration process in dystrophic muscle of male mdx mice. Mice were subjected to low-intensity endurance exercise by running on a motorized Rota-Rod for 5 days/week for 6 weeks. Histomorphological analysis showed a significant reduction of measured inflammatory-necrotic areas in both gastrocnemius and quadriceps muscle of exercised mdx mice as compared to matched sedentary mdx mice. The degenerative-regenerative process was also evaluated by examining the protein levels of connexin 39 (Cx39), a specific gene expressed in injured muscles. Cx39 was not detected in sedentary wild type mice, whereas it was found markedly increased in sedentary mdx mice, revealing active muscle degeneration-regeneration process. These Cx39 protein levels were significantly reduced in muscles of mdx mice exercised for 30 and 40 days, revealing together with histomorphological analysis a strong reduction of degeneration process in mice subjected to low-intensity endurance exercise. Muscles of exercised mdx mice did not show significant changes in force and fatigue resistance as compared to sedentary mdx mice. Overall in this study we found that specific low-intensity endurance exercise induces a beneficial effect probably by reducing the degeneration of dystrophic muscle.

A new field in monkey's frontal cortex: premotor ear-eye field (PEEF).

In macaque monkey, area 8B is cytoarchitectonically considered a transitional area between the granular Brodmann area 9, rostrally, and the rostral part of the dorsal agranular Brodmann area 6, caudally. As for electrophysiological data, microstimulation of area 8B evokes ear and/or eye movements; unit activity recording shows neurons encoding different auditory environmental stimuli and ear and/or eye movements. Moreover, visual attentive fixation modulates the discharge of auditory environmental neurons and auditory-motor neurons. As for anatomical data, area 8B is connected with auditory cortical areas, superior colliculus and cerebellum. Current functional and anatomical evidences support that area 8B is a specific Premotor Ear-Eye Field (PEEF) involved in auditory stimuli recognition and in orienting processes. In conclusion, we suggest that PEEF could play an important role in engaging the auditory spatial attention for the purpose of orienting eye and ear towards the sound source.

Creatine ingestion effects on oxidative stress in a steady-state test at 75% VO(2max).

AIM: The present study was carried out with the aim to analyze the role of creatine on oxidative stress during exercise, i.e. whether creatine is a pro-oxidative or an antioxidant substance. METHODS: In a randomized double-blind study involving 30 adult males, we examined plasma lactate, oxidative stress markers (malondialdehyde, MDA) and glutathione redox ratio (GSSG·GSH-1), antioxidative systems (vitamins A, E, C), and ergospirometric responses (respiratory quotient and relative oxygen uptake) before and after 30 min steady-state tests 75% VO2max (placebo and creatine). RESULTS: Ergospirometric tests, hematocrit values, blood lactate as well as vitamins A, E and C concentrations did not show significant differences between creatine and placebo testing. Conversely, oxidative stress markers MDA and GSSG·GSH-1 increased during placebo trials much more than in creatine trials. CONCLUSION: This is the first report documenting that a creatine loading, i.e., a 0.3 g/kg/die of creatine ingestion for 5 consecutive days, could reduce the oxidative stress, whereas its consumption may not have a clear metabolic advantage in certain aerobic activities.

Therapeutic potential of carbon monoxide in multiple sclerosis.

Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis.

Comparison of neuronal activities of external cuneate nucleus, spinocerebellar cortex and interpositus nucleus during passive movements of the rat's forelimb.

In this paper we examined the neuronal activities of external cuneate nucleus, spinocerebellar Purkinje cells and interpositus nucleus during passive forelimb movements in anesthetized rats with the aim of identifying common or different patterns of activation across structures. By means of principal components analysis, we identified two main patterns of discharge which explained most of the dataset variance. One component characterized the movement-related activity of external cuneate and spinocerebellar cortical neurons, while the other reflected neuronal activity of the interpositus nucleus. We also found that both principal components were related to global forelimb kinematics but, while most of the variance of the activity of external cuneate cells and spinocerebellar Purkinje cells was explained by the limb axis orientation and orientation velocity, interpositus neurons' firing was best related to length and length velocity. This difference in the forelimb kinematics representation observed in external cuneate nucleus and spinocerebellar cortex compared with the interpositus nucleus is discussed with respect to the specific role that these structures may play also during active control of limb movements.

Spatial anisotropy in the encoding of three-dimensional passive limb position by the spinocerebellum.

In an earlier study, we found that the encoding of limb position in the sagittal plane across the population of spinocerebellar Purkinje cells was anisotropic with a preferential gradient along horizontal direction. The aim of this study was to extend to a three-dimensional (3D) workspace the analysis of the relationships between Purkinje cells activity and rat's forelimb spatial position. In anesthetized animals, the extracellular activity of 121 neurons was recorded while a robot passively placed the limb in 18 positions within a cubic workspace (3x3x3 cm). In order to characterize the relationship between spatial locations and Purkinje cell activity we performed a backward stepwise regression starting from a model with three independent variables representing the antero-posterior, the medial-lateral and the vertical axes of workspace. Regression analysis showed that the firing of most cells was modulated exclusively along the antero-posterior (25%) or the medial-lateral (38%) axis, while a small portion was related only to the vertical axis (8%), indicating a generalized nonuniform sensitivity of Purkinje cells to limb displacement in 3D space.

Control of head stability during gait initiation in young and older women.

Transition tasks between static and dynamic situations may challenge head stabilization and balance in older individuals. The study was designed to investigate differences between young and older women in the upper body motion during the voluntary task of gait initiation. Seven young (25+/-2.3 years) and seven older healthy women (78+/-3.4 years) were required to stand on a force platform and initiate walking at their self-selected preferred speed. Angles of head, neck and trunk were measured by motion analysis in the sagittal plane and a cross-correlation analysis was performed on segments pairs. Variability of head and neck angular displacements, as indicated by average standard deviation, was significantly greater in the older than in the young participants. The young women maintained dynamic stability of the upper body, as forward flexion of the trunk was consistently counteracted by coordinated head-neck extension. Differently, movement patterns employed by the older women also included a rigid motion of all upper body segments leaning forward as a single unit. These results demonstrated that older women perform the transition from standing to walking with greater variability in the patterns of upper body motion compared to young women.

Organization of bilateral spinal projections to the lateral reticular nucleus of the rat.

The present study was carried out to analyze the topography of bilateral spinal projections to the lateral reticular nucleus (LRN). We used retrograde transport of fluorescent tracers Fast Blue and Diamidino Yellow to identify spinal neurons projecting to the ipsilateral and/or contralateral LRN, as well as orthograde transport of Phaseolus vulgaris leucoagglutinin to identify the LRN areas where spinoreticular axons terminate. Orthograde labeling confirmed that bilateral spinoreticular projections coming from cervical and upper-thoracic segments terminate in the magnocellular division of LRN, while those coming from the lower-thoracic, lumbar and sacral segments end in the parvocellular division of the nucleus; only a sparse spinal input has been observed in the subtrigeminal division of LRN. Retrograde labeling showed that labeled neurons were present at all spinal levels and in particular large numbers in the cervical and lumbar enlargements. Retrogradely single-labeled cells were located, with contralateral predominance, in all segments of the spinal cord, within laminae IV, V, VI, VIII, and X, whereas in laminae III and VII labeled neurons were mainly observed ipsilaterally. Furthermore, a small fraction of double-labeled cells (7.4%) was observed throughout the spinal cord, mainly in laminae III, IV, VII and VIII.

Blink reflex abnormalities in children with Tourette syndrome.

Tourette syndrome (TS) is a common disorder which typically occurs during childhood or early adolescence. There is no definitive diagnostic test for TS. The objective of this study was to demonstrate whether neurophysiological abnormalities of the blink reflex can be observed in children with TS. We enrolled 15 children with TS, diagnosed according to DSM IV Diagnostic Criteria, and 15 controls. The blink reflex was elicited by stimulating the supraorbital nerve in order to measure the early response (R1), homolateral and contralateral R2 (late) responses, amplitude of R1 and duration of R2. The mean duration of R2 was significantly longer in TS patients than in the controls (P < 0.001, Student's t-test). An abnormal pattern of the blink reflex can be, even in childhood, an early neurophysiologic marker of TS, which is not related to the duration of TS or to the age of onset.

Exercise increases cytochrome oxidase activity in specific cerebellar areas of the rat.

The purpose of this study was to determine whether or not chronic exercise could cause long-term metabolic plasticity in cerebellum. The activity of cytochrome oxidase (COX), coupled to ATP production, reflects long-term plasticity in metabolic capacity. The present study examined whether or not 10 weeks of voluntary exercise would increase COX activity in the cerebellum. Adult male Sprague-Dawley rats were randomly assigned to a control or exercise condition. Exercising rats had running wheels attached to their home cages. COX activity was measured using histochemical methods and optical densitometry. Rats in the exercise condition had significantly higher optical density in spinocerebellum (mainly in lobules 3, 4, 5, 8, 9 and in the copula), but not in neocerebellar crura I and II.

Effects of cerebellar dentate nucleus GABAergic cells on rat inferior olivary neurons.

The present study was undertaken to analyze the effects on unitary activity of inferior olive (IO) neurons elicited by activation of cerebellar lateral nucleus (LN), in rats submitted to the chronic destruction of MDJ structures, i.e. in animals in which the LN-evoked effects in IO should be depended only on activation of GABAergic cells of LN. It has been observed that about two-thirds of the olivocerebellar neurons are significantly affected by LN stimulation, and > 68% of those cells were inhibited. Two-thirds of the inhibitory responses were compatible with a monosynaptic linkage, whereas the remaining inhibitions were probably due to polisynaptic linkages. The majority of LN-induced inhibitions was abolished or greatly reduced following application of GABA antagonists.

Reticulocerebellar projections to the anterior and posterior lobes of the rat cerebellum.

By using retrograde double-labeling techniques, we analyzed the topography of projections from the lateral reticular nucleus (LRN) to the anterior and posterior lobes of the cerebellum, with the aim to investigate whether LRN projections to the two lobes come from different neurons or from branching axons of the same cells. We observed that about 4/5 of afferents the cerebellar cortex come from the ipsilateral LRN and about 1/5 from the contralateral nucleus. Furthermore, magnocellular division of LRN projects mainly to the anterior lobe, whereas parvicellular part primarily to the posterior lobe. The double-labelled cells were very numerous (about 1/3) and were located throughout the LRN, with the higher incidence in the magnocellular division and the lower in the subtrigeminal part.

Effects of Gabapentin and Topiramate in primary rat astrocyte cultures.

We studied in vitro the effects of anticonvulsant drugs Gabapentin and Topiramate on the production of reactive oxygen species and nitric oxide (NO), the activity of glutamine synthetase (GS), and cell viability in primary cultures of rat cortical astrocytes which are intimately involved in the normal functioning of neurons. We investigated the effects of these drugs at concentrations within the therapeutic range (1, 10 and 50 microg/ml). We observed that, in cultured astrocytes, Gabapentin induced a weak increase in the biosynthesis of NO, a mild decrease in GS activity and cell viability, and minor induction of a stress condition. Topiramate was observed to induce even greater stressor effects on these cells.

Tiagabine treatment and DNA damage in rat astrocytes: an in vitro study by comet assay.

We studied in vitro the effects of Tiagabine on genomic DNA of cortical rat astrocytes. To evaluate DNA damage, we used a relatively simple technique called Single Cell Gel Electrophoresis or Comet assay. Tiagabine was dissolved in culture medium and added at concentration of 1, 10, 20 and 50 microg/ml on 12-day old cultured astrocytes. In presence of 1 and 10 microg/ml of Tiagabine, no DNA damage was observed after 48 h of treatment. A moderate DNA damage was instead observed for cells exposed to 20 microg/ml of antiepileptic drug. Finally, DNA fragmentation was more evident after treatment with 50 microg/ml of Tiagabine. We conclude that Tiagabine, at the usual recommended doses, does not appear to influence negatively the cortical rat astrocytes, inducing DNA fragmentation only at very high concentrations.

Distribution of spinocerebellar Purkinje cell responses to passive forelimb movements in the rat.

We recorded Purkinje cell activity throughout the spinocerebellum of anaesthetized rats while imposing circular passive movements to the unrestrained forelimb. The aim was to understand the type of processing of sensory information occurring at the level of the cerebellar cortex, on the basis that precerebellar sensory neurons have been shown to represent whole limb movement parameters better than single joint movements. We observed that neurons representing sensory aspects of arm movements were scattered throughout the spinocerebellar cortex without a distinct segregation from those that did not respond, albeit the relative density of responsive and unresponsive neurons was quite variable and depended on the area of the cortex. Furthermore, Purkinje cells that responded significantly to the arm movement cycles all showed the same response pattern consisting of a firing rate increase during the downward extension of the arm. These results are discussed as suggesting a coordinate framework for the representation of proprioceptive information in the cerebellum congruent to that observed for encoding motor parameters.

C-Fos expression in the basilar pontine nuclei and reticulotegmental nucleus of the rat following lateral cerebellar nucleus stimulation.

The present study was carried out with the aim to observe whether, in the rat, the electric activation of the projection form the cerebellar lateral nucleus (LN) to the basilar pontine nuclei (BPN) and to the reticulotegmental nucleus (RtTg) is capable to induce the c-Fos expression. In particular, we compared the effects of a continuous LN stimulation at low-frequency (tonic stimulation) with those induced by high frequency pulse trains (phasic stimulation). The observed results show that the stimulation of LN induces c-Fos expression in a significant fraction of neurons in the contralateral BPN and RtTg. It was also observed that phasic stimulation was slightly more capable in producing c-Fos expression with respect to the tonic stimulation. Furthermore, systemic injection of MK-801, a non-competitive antagonist of the NMDA receptor, reduced the LN-induced c-Fos expression in BPN and RtTg. In contrast, GYKI 52466, an AMPA/kainate receptor antagonist, did not change the LN driven induction of c-Fos in both BPN and RtTg.

Biological effects of tiagabine on primary cortical astrocyte cultures of rat.

Biological effects of tiagabine, a new antiepileptic drug, were analyzed on cultures of rat's cortical astrocytes. Tiagabine was added to the cultures at concentrations of 1 and 10 microg/ml, correspondent to therapeutic range; cell viability (tetrazolium salt assay and lactic dehydrogenase release), maturation and differentiation (glutamine synthetase activity) and presence of stress conditions (reactive oxygen species formation, inducible nitric oxide synthetase expression and 70 kDa heath shock protein production) were tested. Our results indicate that the addition of Tiagabine to primary astrocytes not only did not change significantly the examined metabolic activities but also seems to exert a protective action against oxidative stress. Thus, our data reinforce the idea that Tiagabine may be considered an effective promising drug in the treatment of epilepsy.

Sensory representation of passive movement kinematics by rat's spinocerebellar Purkinje cells.

In this paper we examined Purkinje cells' sensory representations of kinematic parameters of passive movements imposed to the forelimb of anesthetized rats. Simple spike Purkinje cell activity was recorded while the rat's ipsilateral forearm was moved passively along circular footpaths at two different speeds. We found that the activity of 35.33% (165/467) of the neurons was significantly modulated during movement cycles. A multivariate regression analysis indicated that movement direction was the predominant factor in determining Purkinje cell activity, whereas movement velocity (i.e. the combination of movement direction and speed) was represented to a much lesser degree. Based on this result, we might suggest that a cortical efferent copy is necessary to the cerebellum in order to elaborate a movement velocity signal.