Dependence of Neuroprosthetic Stimulation on the Sensory Modality of the Trigeminal Neurons Following Nerve Injury. Implications in the Design of Future Sensory Neuroprostheses for Correct Perception and Modulation of Neuropathic Pain

Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by in situ hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase “rearranged during transfection”), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100∗(left–right)/right)]. Intra-group differences were studied by paired t-tests. For inter-group comparisons ANOVA test followed by post hoc LSD test (when P < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation

Substitution of natural sensory input by artificial neurostimulation of an amputated trigeminal nerve does not prevent the degeneration of basal forebrain cholinergic circuits projecting to the somatosensory cortex

Peripheral deafferentation downregulates acetylcholine (ACh) synthesis in sensory cortices. However, the responsible neural circuits and processes are not known. We irreversibly transected the rat infraorbital nerve and implanted neuroprosthetic microdevices for proximal stump stimulation, and assessed cytochrome-oxidase and choline- acetyl-transferase (ChAT) in somatosensory, auditory and visual cortices; estimated the number and density of ACh-neurons in the magnocellular basal nucleus (MBN); and localized down-regulated ACh-neurons in basal forebrain using retrograde labeling from deafferented cortices. Here we show that nerve transection, causes down regulation of MBN cholinergic neurons. Stimulation of the cut nerve reverses the metabolic decline but does not affect the decrease in cholinergic fibers in cortex or cholinergic neurons in basal forebrain. Artifical stimulation of the nerve also has no affect of ACh-innervation of other cortices. Cortical ChAT depletion is due to loss of corticopetal MBN ChAT-expressing neurons. MBN ChAT downregulation is not due to a decrease of afferent activity or to a failure of trophic support. Basalocortical ACh circuits are sensory specific, ACh is provided to each sensory cortex “on demand” by dedicated circuits. Our data support the existence of a modality-specific cortex-MBN-cortex circuit for cognitive information processing

Neural activity in the lower pathway of the somatosensory system in the presence of silicon interfaces

In this communication, we present results of experimental work carried out in the frame of the ROSANA project aiming at the investigation of the interactions between sensory inputs and the activity of Central Nervous System (CNS) neurons in the creation of the internal representations of real-world stimuli. We implanted sieve microelectrodes in the peripheral nerve of rats and we obtained functional regeneration of the sensory nerves. We recorded the electrical activity of the regenerated nerve fibers and also of the relay neurons of the first station of the somatosensory pathway. Finally we developed mathematical models of the oscillatory neurons involved in the information processing that fit well with our experimental data

Combining BMI Stimulation and Mathematical Modeling for Acute Stroke Recovery and Neural Repair

Rehabilitation is a neural plasticity-exploiting approach that forces undamaged neural circuits to undertake the functionality of other circuits damaged by stroke. It aims to partial restoration of the neural functions by circuit remodeling rather than by the regeneration of damaged circuits. The core hypothesis of the present paper is that – in stroke – brain machine interfaces (BMIs) can be designed to target neural repair instead of rehabilitation. To support this hypothesis we first review existing evidence on the role of endogenous or externally applied electric fields on all processes involved in CNS repair. We then describe our own results to illustrate the neuroprotective and neuroregenerative effects of BMI-electrical stimulation on sensory deprivation-related degenerative processes of the CNS. Finally, we discuss three of the crucial issues involved in the design of neural repair-oriented BMIs: when to stimulate, where to stimulate and – the particularly important but unsolved issue of – how to stimulate. We argue that optimal parameters for the electrical stimulation can be determined from studying and modeling the dynamics of the electric fields that naturally emerge at the central and peripheral nervous system during spontaneous healing in both, experimental animals and human patients. We conclude that a closed-loop BMI that defines the optimal stimulation parameters from a priori developed experimental models of the dynamics of spontaneous repair and the on-line monitoring of neural activity might place BMIs as an alternative or complement to stem-cell transplantation or pharmacological approaches, intensively pursued nowadays

Stability of Neural Firing in the Trigeminal Nuclei under Mechanical Whisker Stimulation

Sensory information handling is an essentially nonstationary process even under a periodic stimulation. We show how the time evolution of ridges in the wavelet spectrum of spike trains can be used for quantification of the dynamical stability of the neuronal responses to a stimulus. We employ this method to study neuronal responses in trigeminal nuclei of the rat provoked by tactile whisker stimulation. Neurons from principalis (Pr5) and interpolaris (Sp5i) show the maximal stability at the intermediate (50 ms) stimulus duration, whereas Sp5o cells “prefer” shorter (10 ms) stimulation. We also show that neurons in all three nuclei can perform as stimulus frequency filters. The response stability of about 33% of cells exhibits low-pass frequency dynamics. About 57% of cells have band-pass dynamics with the optimal frequency at 5 Hz for Pr5 and Sp5i, and 4 Hz for Sp5o, and the remaining 10% show no prominent dependence on the stimulus frequency. This suggests that the neural coding scheme in trigeminal nuclei is not fixed, but instead it adapts to the stimulus characteristics

Hydrogels-Assisted Cell Engraftment for Repairing the Stroke-Damaged Brain: Chimera or Reality

The use of advanced biomaterials as a structural and functional support for stem cells-based therapeutic implants has boosted the development of tissue engineering applications in multiple clinical fields. In relation to neurological disorders, we are still far from the clinical reality of restoring normal brain function in neurodegenerative diseases and cerebrovascular disorders. Hydrogel polymers show unique mechanical stiffness properties in the range of living soft tissues such as nervous tissue. Furthermore, the use of these polymers drastically enhances the engraftment of stem cells as well as their capacity to produce and deliver neuroprotective and neuroregenerative factors in the host tissue. Along this article, we review past and current trends in experimental and translational research to understand the opportunities, benefits, and types of tentative hydrogel-based applications for the treatment of cerebral disorders. Although the use of hydrogels for brain disorders has been restricted to the experimental area, the current level of knowledge anticipates an intense development of this field to reach clinics in forthcoming years

Silk Fibroin: An Ancient Material for Repairing the Injured Nervous System

Silk refers to a family of natural fibers spun by several species of invertebrates such as spiders and silkworms. In particular, silkworm silk, the silk spun by Bombyx mori larvae, has been primarily used in the textile industry and in clinical settings as a main component of sutures for tissue repairing and wound ligation. The biocompatibility, remarkable mechanical performance, controllable degradation, and the possibility of producing silk-based materials in several formats, have laid the basic principles that have triggered and extended the use of this material in regenerative medicine. The field of neural soft tissue engineering is not an exception, as it has taken advantage of the properties of silk to promote neuronal growth and nerve guidance. In addition, silk has notable intrinsic properties and the by-products derived from its degradation show anti-inflammatory and antioxidant properties. Finally, this material can be employed for the controlled release of factors and drugs, as well as for the encapsulation and implantation of exogenous stem and progenitor cells with therapeutic capacity. In this article, we review the state of the art on manufacturing methodologies and properties of fiber-based and non-fiber-based formats, as well as the application of silk-based biomaterials to neuroprotect and regenerate the damaged nervous system. We review previous studies that strategically have used silk to enhance therapeutics dealing with highly prevalent central and peripheral disorders such as stroke, Alzheimer’s disease, Parkinson’s disease, and peripheral trauma. Finally, we discuss previous research focused on the modification of this biomaterial, through biofunctionalization techniques and/or the creation of novel composite formulations, that aim to transform silk, beyond its natural performance, into more efficient silk-based-polymers towards the clinical arena of neuroprotection and regeneration in nervous system diseases

Atlas electrónico de registros de retinográficos y tomográficos: cribado, derivación, y modelización matématica. Parte III: Retinopatía Diabética

El objetivo de este proyecto es continuar con el Atlas retinográfico iniciado en las convocatorias anteriores con imágenes obtenidas con los principales y novedosos instrumentos utilizados en la actualidad para el diagnóstico de patologías retinianas. El Atlas presentará, además de las imágenes, una detallada descripción de los aspectos que debe tenerse en cuenta en el momento de realizar el cribado. Y además, se realizará un novedoso modelizado matemático de las imágenes. Esta tercera parte se centrará en el diagnóstico de RETINOPATÍAS DIABÉTICAS, una patología con una prevalencia del 4% de la población en general y que constituye una de las primeras causas de ceguera no reversible en los países desarrollados, causando incapacidad laboral permanente. El Atlas puede ser de gran interés para los enfermos de DIABETES ya que está probado que el 100% de los afectados a los 15 años padecen RETINOPATÍAS DIABÉTICAS. Por lo que conviene que sepan el estado del fondo de su ojo. Estará constituida por una extensa relación de retinografías (fotografías del fondo de ojo – retina) y tomografías de coherencia óptica (imágenes de cortes histológicos de la retina en vivo), exponiendo casos reales de patologías comunes y poco comunes. Constituye una herramienta con triple función: por un lado será un elemento didáctico para el aprendizaje de patologías retinianas y el método de diagnóstico por imagen; en segundo lugar, podrá utilizarse para realizar evaluaciones tipo test; y, en tercer lugar, constituirá una completa base de datos que podrá ser utilizado como material de consulta y diagnóstico comparado en la práctica clínica. En definitiva, se trata de una herramienta muy económica de gran utilidad para un amplio grupo de profesionales sanitarios expertos y especialistas en visión y en sistema ocular

Cortical Reshaping and Functional Recovery Induced by Silk Fibroin Hydrogels-Encapsulated Stem Cells Implanted in Stroke Animals

The restitution of damaged circuitry and functional remodeling of peri-injured areas constitute two main mechanisms for sustaining recovery of the brain after stroke. In this study, a silk fibroin-based biomaterial efficiently supports the survival of intracerebrally implanted mesenchymal stem cells (mSCs) and increases functional outcomes over time in a model of cortical stroke that affects the forepaw sensory and motor representations. We show that the functional mechanisms underlying recovery are related to a substantial preservation of cortical tissue in the first days after mSCs-polymer implantation, followed by delayed cortical plasticity that involved a progressive functional disconnection between the forepaw sensory (FLs1) and caudal motor (cFLm1) representations and an emergent sensory activity in peri-lesional areas belonging to cFLm1. Our results provide evidence that mSCs integrated into silk fibroin hydrogels attenuate the cerebral damage after brain infarction inducing a delayed cortical plasticity in the peri-lesional tissue, this later a functional change described during spontaneous or training rehabilitation-induced recovery. This study shows that brain remapping and sustained recovery were experimentally favored using a stem cell-biomaterial-based approach

Atlas electrónico de registros retinográficos y tomográficos: cribado, derivación, diagnóstico diferencial y seguimiento de afecciones retinianas Parte IV: Retinopatía del Prematuro

El objetivo de este proyecto es continuar con el Atlas retinográfico iniciado en las convocatorias anteriores con imágenes obtenidas con los principales y novedosos instrumentos utilizados en la actualidad para el diagnóstico de patologías retinianas. El Atlas presenta, además de las imágenes, una detallada descripción de los criterios cribado. Esta cuarta parte se centra en el diagnóstico por imagen de la retinopatía del prematuro, que se define como una vitreorretinopatía fibro y vasoproliferativa periférica que acontece en los recién nacidos inmaduros, generalmente sometidos a oxigenoterapia. El Atlas está constituido por una extensa relación de retinografías (fotografías del fondo de ojo–retina) y tomografías de coherencia óptica (imágenes de cortes histológicos de la retina en vivo), exponiendo casos reales de patologías comunes y poco comunes. Constituye una herramienta con triple función: por un lado, será un elemento didáctico para el aprendizaje de patologías retinianas y el método de diagnóstico por imagen; en segundo lugar, puede utilizarse para realizar autoevaluaciones y, en tercer lugar, constituye una completa base de datos de casos clínicos. En definitiva, se trata de una herramienta muy económica y de gran utilidad para un amplio grupo de profesionales sanitarios expertos y especialistas en sistema visual