Transcranial static magnetic stimulation reduces seizures in a mouse model of Dravet syndrome.

Dravet syndrome is a rare form of severe genetic epilepsy characterized by recurrent and long-lasting seizures. It appears around the first year of life, with a quick evolution toward an increase in the frequency of the seizures, accompanied by a delay in motor and cognitive development, and does not respond well to antiepileptic medication. Most patients carry a mutation in the gene SCN1A encoding the α subunit of the voltage-gated sodium channel Nav1.1, resulting in hyperexcitability of neural circuits and seizure onset. In this work, we applied transcranial static magnetic stimulation (tSMS), a non-invasive, safe, easy-to-use and affordable neuromodulatory tool that reduces neural excitability in a mouse model of Dravet syndrome. We demonstrate that tSMS dramatically reduced the number of crises. Furthermore, crises recorded in the presence of the tSMS were shorter and less intense than in the sham condition. Since tSMS has demonstrated its efficacy at reducing cortical excitability in humans without showing unwanted side effects, in an attempt to anticipate a possible use of tSMS for Dravet Syndrome patients, we performed a numerical simulation in which the magnetic field generated by the magnet was modeled to estimate the magnetic field intensity reached in the cerebral cortex, which could help to design stimulation strategies in these patients. Our results provide a proof of concept for nonpharmacological treatment of Dravet syndrome, which opens the door to the design of new protocols for treatment.

Cross-modal reaction of auditory and visual cortices after long-term bilateral hearing deprivation in the rat.

Visual cortex (VC) over-activation analysed by evoked responses has been demonstrated in congenital deafness and after long-term acquired hearing loss in humans. However, permanent hearing deprivation has not yet been explored in animal models. Thus, the present study aimed to examine functional and molecular changes underlying the visual and auditory cross-modal reaction. For such purpose, we analysed cortical visual evoked potentials (VEPs) and the gene expression (RT-qPCR) of a set of markers for neuronal activation (c-Fos) and activity-dependent homeostatic compensation (Arc/Arg3.1). To determine the state of excitation and inhibition, we performed RT-qPCR and quantitative immunocytochemistry for excitatory (receptor subunits GluA2/3) and inhibitory (GABAA-α1, GABAB-R2, GAD65/67 and parvalbumin-PV) markers. VC over-activation was demonstrated by a significant increase in VEPs wave N1 and by up-regulation of the activity-dependent early genes c-Fos and Arc/Arg3.1 (thus confirming, by RT-qPCR, our previously published immunocytochemical results). GluA2 gene and protein expression were significantly increased in the auditory cortex (AC), particularly in layers 2/3 pyramidal neurons, but inhibitory markers (GAD65/67 and PV-GABA interneurons) were also significantly upregulated in the AC, indicating a concurrent increase in inhibition. Therefore, after permanent hearing loss in the rat, the VC is not only over-activated but also potentially balanced by homeostatic regulation, while excitatory and inhibitory markers remain imbalanced in the AC, most likely resulting from changes in horizontal intermodal regulation.

Central fatigue induced by short-lasting finger tapping and isometric tasks: A study of silent periods evoked at spinal and supraspinal levels.

The neural substrates of fatigue induced by muscular activity have been addressed in depth in relation to isometric tasks. For these activities, when fatigue develops, it has been noted that the duration of the silent periods (SPs) increases in response to both transcranial magnetic stimulation (TMS) of primary motor cortex or electric cervicomedullary stimulation (CMS). However, fatigue is known to be task-dependent and the mechanisms giving rise to a decrease in motor performance during brief, fast repetitive tasks have been less studied. We hypothesized that fatigue induced by repetitive fast finger tapping may have physiological mechanisms different from those accounting for fatigue during an isometric contraction, even in cases of matched effort durations. In these tasks, we examined the contribution of spinal and supraspinal motor circuits to the production of fatigue. The tapping rate and maximal voluntary contractions (MVC), and TMS- and CMS-evoked SPs were obtained at the time of fatigue, and while subjects maintained maximal muscle activation after fast finger-tapping (or isometric activity) of different durations (10 or 30s). Results showed different mechanisms of fatigue triggered by isometric contraction and repetitive movements, even of short duration. Short-lasting repetitive movements induce fatigue within intracortical inhibitory circuits. They increased TMS-SPs, but not CMS-SPs. On the other hand, isometric contraction had a clear impact on spinal circuits. The consideration of these differences might help to optimize the study of fatigue in physiological conditions and neurological disorders.

Spectroscopic measurement of cortical nitric oxide release induced by ascending activation.

The transition from sleep to the awake state is regulated by the activation of subcortical nuclei of the brainstem (BS) and basal forebrain (BF), releasing acetylcholine and glutamate throughout the cortex and inducing a tonic state of neural activity. It has been suggested that such activation is also mediated by the massive and diffuse cortical release of nitric oxide (NO). In this work we have combined the spectroscopic measurement of NO levels in the somatosensory cortex of the cat through its marker methemoglobin, as well as two other hemodynamic markers (oxyhemoglobin--oxyHb--and deoxyhemoglobin--deoxyHb), together with the electrical stimulation of BS and BF--to induce an experimental transition from a sleep-like state to an awake-like mode. The results show an increase of NO levels either after BS or BF activation. The response induced by BS stimulation was biphasic in the three studied markers, and lasted for up to 30s. The changes induced by BF were monophasic lasting for up to 20s. The systemic blockade of NO production abolished the observed responses to BS whereas responses to BF stimulation were much less affected. These results indicate a crucial role for NO in the neuronal activation induced by the ascending systems.

Anandamide activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus.

The endocannabinoid system is a modulatory system that has been strongly associated with the regulation of functions as learning and memory, pain perception and sensory physiology in many areas of the central nervous system. However, although a role in sensory processing has been demonstrated at the level of the thalamus, the influence of the endocannabinoid system on thalamic rhythms and oscillations has been less studied, despite the fact that such activities are significant characteristics of the thalamic state. The present work aimed to characterize the role of anandamide (AEA) - one of the endogenous CB1 receptor agonists - and AM251 - a CB1 antagonist - in the modulation of burst firing and oscillatory activity present in the dLGN of the anesthetized rat. Administration of AEA (0.5mg/kg iv) increased the number of bursts in the majority of the cells tested and induced the appearance of a slow delta-like (1.5Hz) oscillatory activity. These effects were CB1-mediated, as demonstrated by the complete antagonism during the co-application of AM251 (0.5mg/kg iv). Thus, by demonstrating that the AEA-mediated activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus our study infers that endocannabinoids could have a role in processes controlling the sleep-wake cycle and level of arousal.

Responses of primate LGN cells to moving stimuli involve a constant background modulation by feedback from area MT.

The feedback connections from the cortical middle temporal (MT) motion area, to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re-entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus.

Changes in EMG activity during clenching in chronic pain patients with unilateral temporomandibular disorders.

The study assessed the differences in electromyographic (EMG) activity recorded during clenching in women with chronic unilateral temporomandibular disorders (TMDs) as compared to control subjects. Seventy-five full dentate, normo-occlusion, right-handed, similarly aged female subjects were recruited. Twenty five subjects presented with right side TMD, 25 presented with left side TMD and 25 pain-free control subjects participated. Using integrated surface EMG over a 1 s contraction, the anterior temporalis and masseter muscles were evaluated bilaterally while subjects performed maximum voluntary clenching. Lower EMG activation was observed in patients with TMD as compared to control subjects (temporalis: 195.74+/-18.57 vs. 275.74+/-22.11, P=0.011; masseters: 151.09+/-17.37 vs. 283.29+/-31.87, P<0.001). An asymmetry index (SAI) was calculated to determine ratios of right to left sided activation. Patients with right-sided TMD demonstrated preferential use of their left-sided muscles (SAI -5.35+/-4.02) whereas patients with left-sided TMD demonstrated preferential use of their right-sided muscles (SAI 6.95+/-2.82), (P=0.016). This unilateral reduction in temporalis and masseter activity could be considered as a specific protective functional adaptation of the neuromuscular system due to nociceptive input. The asymmetry index (SAI) may be a useful measure in discriminating patients with right vs. left-sided TMD.

El mundo visual: percibiendo el futuro / The visual world: perceiving the future

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[How does the brain wake up? The nitric oxide blow]. / Como se despierta el cerebro? El soplo del oxido nitrico.

INTRODUCTION: A synthesis of the role of the neuromodulator nitric oxide (NO) on the sleep-wake cycle control is made, emphasizing the function of the activating ascending pathways implicated in arousal. DEVELOPMENT: There are some hypotheses regarding the role of sleep: memory consolidation, ecological factors, cellular repair and nervous system development. The sleep-wake cycle is an active process, modulated by subcortical regions (mesopontine nuclei, diencephalon and basal forebrain) with connections and reciprocal interactions among them. NO is released by neurons and terminals of the sleep-wake cycle modulatory nuclei. The role of NO in this cycle is mainly linked to activation processes: transition to and maintenance of waking and rapid eye movement (REM) sleep. At thalamic level NO is released by cholinergic fibers of the mesopontine nuclei and induces a facilitation of neural responses. In the basal forebrain there exists NO in the cholinergic cells contacting the cortex, suggesting that this ascending pathway can also collaborate in cortical activation through the release of NO. CONCLUSIONS: NO has been identified in neurons of the brain areas controlling the modulation of arousal; hence, this gaseous neuromodulator can have an essential function promoting a quick and global activation of cortical neurons.

¿Cómo se despierta el cerebro? El soplo del óxido nítrico / How does the brain wake up? The nitric oxide blow

Objetivo. Se realiza una síntesis del papel desarrollado por el neuromodulador óxido nítrico (NO) en el control del ciclo sueño-vigilia, con énfasis en los sistemas activadores ascendentes que inducen la transición a la vigilia. Desarrollo. Existen varias hipótesis sobre la función del sueño, entre ellas: consolidación de la memoria, factores ecológicos, reparación celular y desarrollo del sistema nervioso. El ciclo sueño-vigilia es un proceso activo que está modulado por regiones subcorticales (núcleos mesopontinos, diencéfalo y prosencéfalo basal) entre las que se establecen conexiones e interacciones recíprocas. El gas NO se libera en neuronas y terminales de los núcleos moduladores del ciclo sueño-vigilia. El papel del NO en este ciclo está asociado fundamentalmente a los procesos de activación: transición a y mantenimiento de la vigilia y del sueño con movimiento rápido de los ojos (sueño REM). En el tálamo, el NO es liberado por terminales colinérgicas procedentes de los núcleos mesopontinose induce una facilitación de la respuesta neuronal. En el prosencéfalo basal existe NO en las neuronas colinérgicas que contactan con la corteza, por lo que esta ruta ascendente también puede participaren la activación de la corteza mediante la liberación de NO. Conclusiones. El NO está presente en las neuronas de las regiones encefálicas encargadas de modular la transición del sueño a la vigilia; por lo tanto, este neuromodulador gaseoso puede tener una función esencial en potenciar la activación de las neuronas corticales de manera rápida y global (AU)

Introduction. The origin of Tolosa-Hunt syndrome (THS) and orbital pseudotumour (OP) is not fully understood. Itis acknowledged as having an unspecific granulomatous inflammatory nature in different locations. Although there are differences between the clinical features of the two conditions, they also share a number of physiopathogenetic, therapeutic and, in some cases, iconographic similarities. Possible clinical recurrences are common in the two conditions and a broad differential diagnosis is required in all cases. Yet, the association of both processes in the same patient, with radiological proof of the migration of the inflammatory injury, is not frequent. Case report. We report the case of a male patient with a long history of recurring unilateral painful ophthalmoplegia that was sensitive to steroids; criteria for THS were fulfilled and there was later development of homolateral OP, six years after the onset of his symptoms. The findings in serial studies conducted with magnetic resonance imaging must be highlighted. The patient was submitted to a surgical intervention to treat the orbital injury and a chronic inflammatory process was observed in the fibrotic phase. Conclusions. Inflammatory pseudotumour and THSperhaps have more points in common than has traditionally been accepted. To our knowledge few cases of the above-mentioned association have been reported in the same patient. When confronted by cases of painful ophthalmoplegia with excessive recurrences the physician must consider the possibility of other alternative diagnoses (AU)

Evaluation of the effect of training using auditory stimulation on rhythmic movement in Parkinsonian patients--a combined motor and [18F]-FDG PET study.

INTRODUCTION: A programme of rehabilitation using auditory cues has previously been shown to decrease movement variability in the gait of Parkinsonian patients. OBJECTIVE AND METHODS: We studied the temporal variability of finger-tapping and gait in 9 patients with Parkinson's disease (PD) before and after they undertook a physical rehabilitation programme. Positron Emission Tomography (PET) using 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) was performed in these subjects to look for changes in metabolic brain activity after completion of the rehabilitation program. RESULTS: The reduction of variability was seen not only in gait but also other repetitive movements such as finger tapping. Furthermore, here we show differences in resting regional cerebral glucose utilisation in these patients compared to healthy controls (significant hypometabolism-p < 0.001-for the PD group in the right parietal and temporal lobes, left temporal and frontal lobes and a hypermetabolism in the left cerebellum) and specific changes following the improvements in repetitive movement abilities (significant metabolic increment-p < 0.001-in the PD group in the right cerebellum and in the right parietal and temporal lobes). CONCLUSIONS: Although our study does not allow us to draw firm conclusions, it provides new information on the neural basis of auditory stimulation in PD. Our results extend those from previous studies to show improvement in the temporal variability of two types of rhythmic movements after participation by PD patients in a physical rehabilitation programme, along with changes in glucose uptake in several brain areas involved in sensorimotor processing.

A simple procedure using auditory stimuli to improve movement in Parkinson's disease: a pilot study.

It has been suggested that sequential movements in Parkinsonian patients might be improved by the effects of external rhythmic cues, either visual or acoustic, acting as a sort of timekeeper. In line with that idea, we have developed a portable system which allows the patient suffering from bradykinesia and rigidity to initiate appropriate auditory stimulation when he/she is not able to move. Here we present data from six Parkinson's Disease (PD) patients studied with surface electromyography, while walking along an 8.5m walkway. All showed remarkable improvement in the EMG parameters studied while using the device. The results are consistent with prior reports on rhythmic auditory facilitation in Parkinson's disease gait,and suggest that this represents a novel and inexpensive tool to help people afflicted by PD in daily motor performance.

A possible role for nitric oxide at the sleep/wake interface.

Cholinergic neurotransmission is known to have important arousal/activating functions. The neurons responsible for those actions also release the atypical neuromodulator nitric oxide (NO), which has been shown in previous studies to be involved in the modulation of sleep/wake states. The present investigation, using an animal model (anesthetized cat) tests the hypothesis that NO cooperates with ACh in controlling rhythmic neuronal activity, which may play a role in sleep/wake transition. We have used extracellular singleunit recording of neurons in the dorsal thalamus and visual cortex with simultaneous iontophoretic application of drugs acting upon the NO system: the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOArg), NO donors, and 8-bromo-cGMP (which mimics the action of NO). Local inhibition of NOS significantly reduced the activity of recorded cells in both thalamus and visual cortex. The opposite effect was achieved with NO donors application. In cortex, ejection of 8-bromo-cGMP or the NO donor diethylamine-nitric oxide (DEA-NO) increased cell firing. Furthermore, the rhythmic firing pattern present in these cortical neurons was disrupted. Taken together, these findings suggest that the NO system collaborates with cholinergic neurotransmission. This collaboration might be involved in the control of different patterns of electrogenic activity during various states of the sleep-wake cycle, via the ability of the NO system to modify rhythmic activity of neurons.

Visual response augmentation in cat (and macaque) LGN: potentiation by corticofugally mediated gain control in the temporal domain.

Visual responses of neurons are dependent on the context of a stimulus, not only in spatial terms but also temporally, although evidence for temporally separate visual influences is meagre, based mainly on studies in the higher cortex. Here we demonstrate temporally induced elevation of visual responsiveness in cells in the lateral geniculate nucleus (LGN) of cat and monkey following a period of high intensity (elevated contrast) stimulation. This augmentation is seen in 40-70% (monkey-cat) of cells tested and of all subtypes. Peaking at approximately 3 min following the period of intense stimulation, it can last for 10-12 min and can be repeated and summed in time. Furthermore, it is dependent on corticofugal input, is seen even when high contrast stimuli of orthogonal orientation are used and therefore results from a/any prior increase in activity in the retino-geniculo-striate pathway. We suggest that this reflects a general mechanism for control of visual responsiveness; both a flexible and dynamic means of changing effectiveness of thalamic activity as visual input changes, but also a mechanism which is an emergent property of the thalamo-cortico-thalamic loop.

The primate pulvinar nuclei: vision and action.

The pulvinar nuclei of the thalamus are proportionately larger in higher mammals, particularly in primates, and account for a quarter of the total mass. Traditionally, these nuclei have been divided into oral (somatosensory), superior and inferior (both visual) and medial (visual, multi-sensory) divisions. With reciprocal connections to vast areas of cerebral cortex, and input from the colliculus and retina, they occupy an analogous position in the extra-striate visual system to the lateral geniculate nucleus in the primary visual pathway, but deal with higher-order visual and visuomotor transduction. With a renewed recent interest in this thalamic nuclear collection, and growth in our knowledge of the cortex with which it communicates, perhaps the time is right to look to new dimensions in the pulvinar code.

Effects of feedback projections from area 18 layers 2/3 to area 17 layers 2/3 in the cat visual cortex.

In the absence of a direct geniculate input, area 17 cells in the cat are nevertheless able to respond to visual stimuli because of feedback connections from area 18. Anatomic studies have shown that, in the cat visual cortex, layer 5 of area 18 projects to layer 5 of area 17, and layers 2/3 of area 18 project to layers 2/3 of area 17. What is the specific role of these connections? Previous studies have examined the effect of area 18 layer 5 blockade on cells in area 17 layer 5. Here we examine whether the feedback connections from layers 2/3 of area 18 influence the orientation tuning and velocity tuning of cells in layers 2/3 of area 17. Experiments were carried out in anesthetized and paralyzed cats. We blocked reversibly a small region (300 microm radius) in layers 2/3 of area 18 by iontophoretic application of GABA and recorded simultaneously from cells in layers 2/3 of area 17 while stimulating with oriented sweeping bars. Area 17 cells showed either enhanced or suppressed visual responses to sweeping bars of various orientations and velocities during area 18 blockade. For most area 17 cells, orientation bandwidths remained unaltered, and we never observed visual responses during blockade that were absent completely in the preblockade condition. This suggests that area 18 layers 2/3 modulate visual responses in area 17 layers 2/3 without fundamentally altering their specificity.

Sight and insight--on the physiological role of nitric oxide in the visual system.

Research in the fields of cellular communication and signal transduction in the brain has moved very rapidly in recent years. Nitric oxide (NO) is one of the latest discoveries in the arena of messenger molecules. Current evidence indicates that, in visual system, NO is produced in both postsynaptic and presynaptic structures and acts as a neurotransmitter, albeit of a rather unorthodox type. Under certain conditions it can switch roles to become either neuronal 'friend' or 'foe'. Nitric oxide is a gas that diffuses through all physiological barriers to act on neighbouring cells across an extensive volume on a specific time scale. It, therefore,has the opportunity to control the processing of vision from the lowest level of retinal transduction to the control of neuronal excitability in the visual cortex.

Enhanced visual responses in cat dLGN--potentiation by priming with excitatory amino acids.

Sustained iontophoresis of NMDA potentiated visual responses for minutes after the application in 16 of 38 cells (42%), peaking 3 min after the end of the application and declining to control levels within 12 min. Potentiation was also seen after application of ACPD (36%, n = 14) and AMPA (29%, n = 14), but not after application of ACh (n = 20). ACh also excites dLGN cells, but does not interact with amino acid receptors, and ACh receptors are not directly involved in the transmission of visual information. We suggest that this modulation is a form of visually induced potentiation which permits dynamic modification of the strength of visual information to be relayed to the cortex depending upon the history of previous activity levels.