SIGNALING MECHANISMS THAT CONTROL GAP JUNCTIONAL COUPLING BETWEEN RETINAL NEURONS

Gap junctions between neurons form the structural substrate for electrical synapses. Connexin 36 (Cx36, and its non-mammalian ortholog connexin 35) is the major neuronal gap junction protein in the central nervous system (CNS), and contributes to several important neuronal functions including neuronal synchronization, signal averaging, network oscillations, and motor learning. Connexin 36 is strongly expressed in the retina, where it is an obligatory component of the high-sensitivity rod photoreceptor pathway. A fundamental requirement of the retina is to adapt to broadly varying inputs in order to maintain a dynamic range of signaling output. Modulation of the strength of electrical coupling between networks of retinal neurons, including the Cx36-coupled AII amacrine cell in the primary rod circuit, is a hallmark of retinal luminance adaptation. However, very little is known about the mechanisms regulating dynamic modulation of Cx36-mediated coupling. The primary goal of this work was to understand how cellular signaling mechanisms regulate coupling through Cx36 gap junctions. We began by developing and characterizing phospho-specific antibodies against key regulatory phosphorylation sites on Cx36. Using these tools we showed that phosphorylation of Cx35 in fish models varies with light adaptation state, and is modulated by acute changes in background illumination. We next turned our focus to the well-studied and readily identifiable AII amacrine cell in mammalian retina. Using this model we showed that increased phosphorylation of Cx36 is directly related to increased coupling through these gap junctions, and that the dopamine-stimulated uncoupling of the AII network is mediated by dephosphorylation of Cx36 via protein kinase A-stimulated protein phosphatase 2A activity. We then showed that increased phosphorylation of Cx36 on the AII amacrine network is driven by depolarization of presynaptic ON-type bipolar cells as well as background light increments. This increase in phosphorylation is mediated by activation of extrasynaptic NMDA receptors associated with Cx36 gap junctions on AII amacrine cells and by Ca2+-calmodulin-dependent protein kinase II activation. Finally, these studies indicated that coupling is regulated locally at individual gap junction plaques. This work provides a framework for future study of regulation of Cx36-mediated coupling, in which increased phosphorylation of Cx36 indicates increased neuronal coupling.

Improving backdrivability in geared rehabilitation robots

Many rehabilitation robots use electric motors with gears. The backdrivability of geared drives is poor due to friction. While it is common practice to use velocity measurements to compensate for kinetic friction, breakaway friction usually cannot be compensated for without the use of an additional force sensor that directly measures the interaction force between the human and the robot. Therefore, in robots without force sensors, subjects must overcome a large breakaway torque to initiate user-driven movements, which are important for motor learning. In this technical note, a new methodology to compensate for both kinetic and breakaway friction is presented. The basic strategy is to take advantage of the fact that, for rehabilitation exercises, the direction of the desired motion is often known. By applying the new method to three implementation examples, including drives with gear reduction ratios 100-435, the peak breakaway torque could be reduced by 60-80%.

BRAIN ACTIVATION AND CONNECTIVITY IN NON-DISABLED MULTIPLE SCLEROSIS PATIENTS

Multiple sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. There is no cure for MS and current therapies have limited efficacy. While the majority of individuals with MS develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). The current studies combined functional MRI and diffusion tensor imaging (DTI) to elucidate brain mechanisms associated with lack of clinical disability in patients with MS. Recent evidence has implicated cortical reorganization as a mechanism to limit the clinical manifestation of the disease. Functional MRI was used to test the hypothesis that non-disabled MS patients (Expanded Disability Status Scale ≤ 1.5) show increased recruitment of cognitive control regions (dorsolateral prefrontal and anterior cingulate cortex) while performing sensory, motor and cognitive tasks. Compared to matched healthy controls, patients increased activation of cognitive control brain regions when performing non-dominant hand movements and the 2-back working memory task. Using dynamic causal modeling, we tested whether increased cognitive control recruitment is associated with alterations in connectivity in the working memory functional network. Patients exhibited similar network connectivity to that of control subjects when performing working memory tasks. We subsequently investigated the integrity of major white matter tracts to assess structural connectivity and its relation to activation and functional integration of the cognitive control system. Patients showed substantial alterations in callosal, inferior and posterior white matter tracts and less pronounced involvement of the corticospinal tracts and superior longitudinal fasciculi (SLF). Decreased structural integrity within the right SLF in patients was associated with decreased performance, and decreased activation and connectivity of the cognitive control system when performing working memory tasks. These studies suggest that patient with MS without clinical disability increase cognitive control system recruitment across functional domains and rely on preserved functional and structural connectivity of brain regions associated with this network. Moreover, the current studies show the usefulness of combining brain activation data from functional MRI and structural connectivity data from DTI to improve our understanding of brain adaptation mechanisms to neurological disease.

Cerebellar cortex involvement in classical eyelid conditioning

A model for cerebellar involvement in motor learning was tested using classical eyelid conditioning in the rabbit. Briefly, we assume that modifications of the strength of granule cell synapses at Purkinje cells in the cerebellar cortex and mossy fiber (MF) synapses at cerebellar interpositus nuclei are responsible for the acquisition, adaptively-timed expression, and extinction of conditioned eyelid responses (CRs). A corollary of these assumptions is that the cerebellar cortex is necessary for acquisition and extinction. This model also suggests a mechanism whereby the cerebellar cortex can discriminate different times during a conditioned stimulus (CS) and thus mediate the learned timing of CRs. Therefore, experiments were done to determine the role of the cerebellar cortex in the timing, extinction, and acquisition of CRs. Lesions of the cerebellar cortex that included the anterior lobe disrupted the learned timing of CRs such that they occurred at extremely short latencies. Stimulation of MFs in the middle cerebellar peduncle as the CS could support differently timed CRs in the same animal. These data indicate that synaptic plasticity in the cerebellar cortex mediates the learned timing of CRs. These short-latency CRs which resulted from anterior lobe damage did not extinguish, while CRs in animals receiving lesions which did not include the anterior lobe extinguished normally. Preliminary data suggests that lesions of the anterior lobe which produce short-latency responses prevent the acquisition of CRs to a novel CS. These findings indicate that the anterior lobe of cerebellar cortex is necessary for eyelid conditioning. The involvement of the anterior lobe in eyelid conditioning has not been previously reported, however, the anterior lobe has generally been spared in lesion studies examining cerebellar cortex involvement in eyelid conditioning due to its relatively inaccessible location. The observation that the anterior lobe of the cerebellar cortex is not always required for the basic expression of CRs, but is necessary for response timing, extinction, and acquisition, is consistent with the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by Purkinje cell activity. ^

A taste of the technical cuisine: metals and other ingredients

According to cognitive linguistics, language has an experiential origin based on perception, sensory motor activities and our knowledge of the world. Our thought operates by establishing similarities, links and associations that enable us to talk about one thing in terms of another as shown in the example of love as a journey (Lakoff and Johnson, 1980). Metaphor and metonymy are conceptual and linguistic tools that make possible most of these cognitive operations. Since metaphor is an essential element of human communication, the discourse of specialised disciplines includes metaphorical mappings and numerous examples of metaphorical expressions, for example in economics, where business is mapped in terms of war (White, 2004; Herrera & White, 2000), electrotechnics with electrical components understood as couples (Roldán- Riejos in preparation) or in civil engineering where a bridge is conceptualized as a person (Roldán-Riejos, 2013). In this paper, the metaphors: WORKING WITH METALS IS COOKING/ TRABAJAR CON METALES ES COCINAR and METALS ARE CULINARY OBJECTS/ LOS METALES SON OBJETOS CULINARIOS are explored. The main aim is to show that the cooking metaphor is widely spread in the metallurgical domain in English and Spanish, although with different nuances in each language due to socio-cultural factors. The method adopted consists of analysing examples taken from the: Bilingual Dictionary of Scientific and Technical Metaphors and Metonymies Spanish- English/English-Spanish, a forthcoming and rigorously documented bilingual dictionary that sums up research on conceptual, linguistic and visual metaphor and metonymy in different areas of engineering (Roldán-Riejos and Molina, 2013). The present paper studies in detail English and Spanish cross-linguistic correspondences related to types of metals and processes. It is suggested that they reflect synesthetic metaphoric mappings. The exploitation of cognitive conceptual metaphor in the ESP classroom is lastly recommended.

USO DO BRINQUEDO NO ATENDIMENTO FISIOTERAPÊUTICO DE CRIANÇAS COM PARALISIA CEREBRAL

A paralisia cerebral, doença não progressiva, compromete movimentos e postura. A fisioterapia atual volta-se para um tratamento holístico. Brincar proporciona desenvolvimento neuropsicomotor. O presente estudo tem como objetivos investigar a opinião de fisioterapeutas que atuam em neuropediatria sobre a utilização do brinquedo em sua prática clínica e verificar sua possível utilização em intervenções junto a crianças com paralisia cerebral. Utiliza-se inicialmente de questionário de opinião junto a 50 fisioterapeutas das diversas clínicas da Associação de Apoio a Criança com Deficiência, AACD - SP, verificando a utilização de brinquedos face aos diversos objetivos fisioterapeuticos; a seguir, realiza observação de 60 atendimentos, em fisioterapia aquática e de solo, de crianças com paralisia cerebral, identificando a utilização de cada categoria de brinquedo relativo ao objetivo terapêutico. Os dados obtidos no questionário revelaram em ordem decrescente utilização de: brinquedos sensório-motores 57,4%, para ganho de equilíbrio (E); 22,2% para coordenação motora (CM); 18,5% para aquisições posturais (AP) e 2% para relaxamento muscular (RM). Em relação aos jogos de faz-de-conta: 37% (E); 39% (AP) e 24% (CM).Para os jogos de regras: 54% (E); 35% (CM); 11% (AP). Com os jogos de montagem: 52% (CM); 24% (E); 24% (AP). Os dados da observação revelaram que os principais objetivos terapêuticos visados com utilização de brinquedos foram: alongamento, primeiro 10 ; fortalecimento muscular, equilíbrio e treino de marcha de 10 a 40 . Quanto à modalidade de brinquedo observada houve predomínio do faz de conta no início e no fim da sessão e das demais categorias no meio, de forma intercalada. Os dados da observação coincidiram com os do questionário revelando utilização sistemática de brinquedos com objetivos fisioterapeuticos.(AU)

USO DO BRINQUEDO NO ATENDIMENTO FISIOTERAPÊUTICO DE CRIANÇAS COM PARALISIA CEREBRAL

A paralisia cerebral, doença não progressiva, compromete movimentos e postura. A fisioterapia atual volta-se para um tratamento holístico. Brincar proporciona desenvolvimento neuropsicomotor. O presente estudo tem como objetivos investigar a opinião de fisioterapeutas que atuam em neuropediatria sobre a utilização do brinquedo em sua prática clínica e verificar sua possível utilização em intervenções junto a crianças com paralisia cerebral. Utiliza-se inicialmente de questionário de opinião junto a 50 fisioterapeutas das diversas clínicas da Associação de Apoio a Criança com Deficiência, AACD - SP, verificando a utilização de brinquedos face aos diversos objetivos fisioterapeuticos; a seguir, realiza observação de 60 atendimentos, em fisioterapia aquática e de solo, de crianças com paralisia cerebral, identificando a utilização de cada categoria de brinquedo relativo ao objetivo terapêutico. Os dados obtidos no questionário revelaram em ordem decrescente utilização de: brinquedos sensório-motores 57,4%, para ganho de equilíbrio (E); 22,2% para coordenação motora (CM); 18,5% para aquisições posturais (AP) e 2% para relaxamento muscular (RM). Em relação aos jogos de faz-de-conta: 37% (E); 39% (AP) e 24% (CM).Para os jogos de regras: 54% (E); 35% (CM); 11% (AP). Com os jogos de montagem: 52% (CM); 24% (E); 24% (AP). Os dados da observação revelaram que os principais objetivos terapêuticos visados com utilização de brinquedos foram: alongamento, primeiro 10 ; fortalecimento muscular, equilíbrio e treino de marcha de 10 a 40 . Quanto à modalidade de brinquedo observada houve predomínio do faz de conta no início e no fim da sessão e das demais categorias no meio, de forma intercalada. Os dados da observação coincidiram com os do questionário revelando utilização sistemática de brinquedos com objetivos fisioterapeuticos.(AU)

Dynamic characteristics and adaptability of mouse vestibulo-ocular and optokinetic response eye movements and the role of the flocculo-olivary system revealed by chemical lesions

The dynamic characteristics of reflex eye movements were measured in two strains of chronically prepared mice by using an infrared television camera system. The horizontal vestibulo-ocular reflex (HVOR) and horizontal optokinetic response (HOKR) were induced by sinusoidal oscillations of a turntable, in darkness, by 10° (peak to peak) at 0.11–0.50 Hz and of a checked-pattern screen, in light, by 5–20°at 0.11–0.17 Hz, respectively. The gains and phases of the HVOR and HOKR of the C57BL/6 mice were nearly equivalent to those of rabbits and rats, whereas the 129/Sv mice exhibited very low gains in the HVOR and moderate phase lags in the HOKR, suggesting an inherent sensory-motor anomaly. Adaptability of the HOKR was examined in C57BL/6 mice by sustained screen oscillation. When the screen was oscillated by 10° at 0.17 Hz, which induced sufficient retinal slips, the gain of the HOKR increased by 0.08 in 1 h on average, whereas the stimuli that induced relatively small or no retinal slips affected the gain very little. Lesions of the flocculi induced by local applications of 0.1% ibotenic acid and lesions of the inferior olivary nuclei induced by i.p. injection of 3-acetylpyridine in C57BL/6 mice little affected the dynamic characteristics of the HVOR and HOKR, but abolished the adaptation of the HOKR. These results indicate that the olivo-floccular system plays an essential role in the adaptive control of the ocular reflex in mice, as suggested in other animal species. The data presented provide the basis for analyzing the reflex eye movements of genetically engineered mice.

Nitric oxide plays a key role in adaptive control of locomotion in cat

Diverse roles in cellular functions have been ascribed to nitric oxide (NO), and its involvement in induction of long-term depression in cerebellar Purkinje cells has been demonstrated. Manipulations of NO concentration or its synthesis in cerebellar tissues therefore provide a means for investigating roles of NO in cerebellar functions at both cellular and behavioral levels. We tested adaptive control of locomotion to perturbation in cats, and found that this form of motor learning was abolished by application of either an inhibitor of NO synthase or a scavenger of NO to the cerebellar cortical locomotion area. This finding supports the view that NO in the cerebellum plays a key role in motor learning.

Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Knock-in mice were generated that harbored a leucine-to-serine mutation in the α4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.

Visual Manifestations of Primary Metaphors Through Mise-en-scène Techniques

Grady distinguishes two main types of metaphor in order to provide a solution in the controversies stemming from the conceptual theory of metaphor: correlation-based metaphors and resemblance metaphors. In “correlation-based metaphors”, the source domain is sensory-motor, while the target domain is not. On the contrary, “resemblance metaphors” are originated by a physical or conceptual perception which is common in both domains, by the association of concepts with common features. Primary metaphors are the minimal units of correlation-based metaphors; they are inherent in human nature and the result of the nature of our brain, our body and the world that we inhabit. We acquire them automatically and we cannot avoid them. Furthermore, as corporal experiences are universal, so are primary metaphors. In this paper, I will argue that primary metaphors manifest themselves visually through scene-setting techniques such as composition, framing, camera movement or lighting. Film-makers can use the different aspects of mise-en-scène metaphorically in order to express abstract notions like evil, importance, control, relationship or confusion. Such visual manifestations, as also occurs with their verbal equivalents, frequently go unnoticed or have been used so often that they have become clichés. But the important thing to bear in mind is that their origin lies in a primary metaphor and due to this origin these kinds of film-making strategies have been so expressively successful.

Novel strategies in feedforward adaptation to a position-dependent perturbation

To investigate the control mechanisms used in adapting to position-dependent forces, subjects performed 150 horizontal reaching movements over 25 cm in the presence of a position-dependent parabolic force field (PF). The PF acted only over the first 10 cm of the movement. On every fifth trial, a virtual mechanical guide (double wall) constrained subjects to move along a straight-line path between the start and target positions. Its purpose was to register lateral force to track formation of an internal model of the force field, and to look for evidence of possible alternative adaptive strategies. The force field produced a force to the right, which initially caused subjects to deviate in that direction. They reacted by producing deviations to the left, into the force field, as early as the second trial. Further adaptation resulted in rapid exponential reduction of kinematic error in the latter portion of the movement, where the greatest perturbation to the handpath was initially observed, whereas there was little modification of the handpath in the region where the PF was active. Significant force directed to counteract the PF was measured on the first guided trial, and was modified during the first half of the learning set. The total force impulse in the region of the PF increased throughout the learning trials, but it always remained less than that produced by the PF. The force profile did not resemble a mirror image of the PF in that it tended to be more trapezoidal than parabolic in shape. As in previous studies of force-field adaptation, we found that changes in muscle activation involved a general increase in the activity of all muscles, which increased arm stiffness, and selectively-greater increases in the activation of muscles which counteracted the PF. With training, activation was exponentially reduced, albeit more slowly than kinematic error. Progressive changes in kinematics and EMG occurred predominantly in the region of the workspace beyond the force field. We suggest that constraints on muscle mechanics limit the ability of the central nervous system to employ an inverse dynamics model to nullify impulse-like forces by generating mirror-image forces. Consequently, subjects adopted a strategy of slightly overcompensating for the first half of the force field, then allowing the force field to push them in the opposite direction. Muscle activity patterns in the region beyond the boundary of the force field were subsequently adjusted because of the relatively-slow response of the second-order mechanics of muscle impedance to the force impulse.

The use of real-time ultrasound imaging for biofeedback of lumbar multifudus muscle contraction in healthy subjects

Study Design: Randomized controlled trial. Objective: To determine if the provision of visual biofeedback using real-time ultrasound imaging enhances the ability to activate the multifidus muscle. Background: Increasingly clinicians are using real-time ultrasound as a form of biofeedback when re-educating muscle activation. The effectiveness of this form of biofeedback for the multifidus muscle has not been reported. Methods and Measures: Healthy subjects were randomly divided into groups that received different forms of biofeedback. All subjects received clinical instruction on how to activate the multifidus muscle isometrically prior to testing and verbal feedback regarding the amount of multifidus contraction, which occurred during 10 repetitions (acquisition phase). In addition, 1 group received visual biofeedback (watched the multifidus muscle contract) using real-time ultrasound imaging. All subjects were reassessed a week later (retention phase). Results: Subjects from both groups improved their voluntary contraction of the multifidus muscle in the acquisition phase (P

Disrupted cortical proprioceptive representation evokes symptoms of peculiarity, foreignness and swelling, but not pain

Objectives. It has been proposed that disruption of the internal proprioceptive representation, via incongruent sensory input, may underpin pathological pain states, but experimental evidence relies on conflicting visual input, which is not clinically relevant. We aimed to determine the symptomatic effect of incongruent proprioceptive input, imparted by vibration of the wrist tendons, which evokes the illusion of perpetual wrist flexion and disrupts cortical proprioceptive representation. Methods. Twenty-nine healthy and naive volunteers reported symptoms during five conditions: control, active and passive wrist flexion, extensor carpi radialis tendon vibration to evoke illusion of perpetual wrist flexion, and ulnar styloid (sham) vibration. No advice was given about possible illusions. Results. Twenty-one subjects reported the illusion of perpetual wrist flexion during tendon vibration. There was no effect of condition or of whether or not subjects reported an illusion on discomfort/pain (P > 0.28). Peculiarity, swelling and foreignness were greater during tendon vibration than during the other conditions, and greater during tendon vibration in those who reported an illusion of wrist flexion than in those who did not (P < 0.05 for all). Symptoms were reported by at least two subjects in each condition and four subjects reported systemic symptoms (e.g. nausea). Conclusions. In healthy volunteers, incongruent proprioceptive input does not cause discomfort or pain but does evoke feelings of peculiarity, swelling and foreignness in the limb.

Ipsilateral corticocortical projections to the primary and middle temporal visual areas of the primate cerebral cortex: area-specific variations in the morphology of connectionally identified pyramidal cells

We quantified the morphology of over 350 pyramidal neurons with identified ipsilateral corticocortical projections to the primary (V1) and middle temporal (MT) visual areas of the marmoset monkey, following intracellular injection of Lucifer Yellow into retrogradely labelled cells. Paralleling the results of studies in which randomly sampled pyramidal cells were injected, we found that the size of the basal dendritic tree of connectionally identified cells differed between cortical areas, as did the branching complexity and spine density. We found no systematic relationship between dendritic tree structure and axon target or length. Instead, the size of the basal dendritic tree increased roughly in relation to increasing distance from the occipital pole, irrespective of the length of the connection or the cortical layer in which the neurons were located. For example, cells in the second visual area had some of the smallest and least complex dendritic trees irrespective of whether they projected to V1 or MT, while those in the dorsolateral area (DL) were among the largest and most complex. We also observed that systematic differences in spine number were more marked among V1-projecting cells than MT-projecting cells. These data demonstrate that the previously documented systematic differences in pyramidal cell morphology between areas cannot simply be attributed to variable proportions of neurons projecting to different targets, in the various areas. Moreover, they suggest that mechanisms intrinsic to the area in which neurons are located are strong determinants of basal dendritic field structure.