Male gonadal denervation by guanethidine at pre-puberty: Different doses, different results. The intervention of the pineal deafferentation

Since gonadal denervation and pineal deafferentation by cervical superior ganglionectomy affect sexual development, this study was performed to evaluate testicular steroidogenesis, spermatogenesis and the cervical superior ganglion (CSG) histology in rats treated with guanethidine (GD). The treatment was performed by GD s.c. injections for 3 weeks, from the 21st day of age to the 41st day of age (pre-puberty), when the animals were sacrificed. Different doses were used: group A=10 mg/kg/day, group B=50 mg/kg/day and saline (control group). Testicular denervation was confirmed by HPLC for catecholamines in testicular tissue. Testicular concentrations (TC) of progesterone (P4) and testosterone (T) were measured by RIA. Significantly higher TC of P4 and lower TC of T were observed only in group A in comparison with group B and the control group. No alteration of sperm production was observed in either treated group. Histological analysis of CSG showed only few neuronal alterations in group A rats, while in group B the nervous cells were practically destroyed. This suggests that 10 mg/kg/day GD treatment probably produces a specific blockade of 17 alpha-hydroxylase/17,20 desmolase at pre-puberty leading to a decrease of the androgen production. However, in the 50 mg/kg/day group no differences were observed concerning the steroid profiles, this result being attributed to the extensive damage to the CSG observed only in group B. The CSG destruction causes deafferentation of the pineal gland producing abolishment of the inhibition of the 17 alpha-hydroxylase/17,20 desmolase promoted by melatonin or by an out of phase production of androgen.

Compensatory saccades benefit from prediction during head impulse testing in early recovery from vestibular deafferentation

The head impulse test (HIT) can identify a deficient vestibulo-ocular reflex (VOR) by the compensatory saccade (CS) generated once the head stops moving. The inward HIT is considered safer than the outward HIT, yet might have an oculomotor advantage given that the subject would presumably know the direction of head rotation. Here, we compare CS latencies following inward (presumed predictable) and outward (more unpredictable) HITs after acute unilateral vestibular nerve deafferentation. Seven patients received inward and outward HITs delivered at six consecutive postoperative days (POD) and again at POD 30. All head impulses were recorded by portable video-oculography. CS included those occurring during (covert) or after (overt) head rotation. Inward HITs included mean CS latencies (183.48 ms ± 4.47 SE) that were consistently shorter than those generated during outward HITs in the first 6 POD (p = 0.0033). Inward HITs induced more covert saccades compared to outward HITs, acutely. However, by POD 30 there were no longer any differences in latencies or proportions of CS and direction of head rotation. Patients with acute unilateral vestibular loss likely use predictive cues of head direction to elicit early CS to keep the image centered on the fovea. In acute vestibular hypofunction, inwardly applied HITs may risk a preponderance of covert saccades, yet this difference largely disappears within 30 days. Advantages of inwardly applied HITs are discussed and must be balanced against the risk of a false-negative HIT interpretation.

Combined VEGF and PDGF treatment reduces secondary degeneration after spinal cord injury

Trauma to the spinal cord creates an initial physical injury damaging neurons, glia, and blood vessels, which then induces a prolonged inflammatory response, leading to secondary degeneration of spinal cord tissue, and further loss of neurons and glia surrounding the initial site of injury. Angiogenesis is a critical step in tissue repair, but in the injured spinal cord angiogenesis fails; blood vessels formed initially later regress. Stabilizing the angiogenic response is therefore a potential target to improve recovery after spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) can initiate angiogenesis, but cannot sustain blood vessel maturation. Platelet-derived growth factor (PDGF) can promote blood vessel stability and maturation. We therefore investigated a combined application of VEGF and PDGF as treatment for traumatic spinal cord injury, with the aim to reduce secondary degeneration by promotion of angiogenesis. Immediately after hemisection of the spinal cord in the rat we delivered VEGF and PDGF and to the injury site. One and 3 months later the size of the lesion was significantly smaller in the treated group compared to controls, and there was significantly reduced gliosis surrounding the lesion. There was no significant effect of the treatment on blood vessel density, although there was a significant reduction in the numbers of macrophages/microglia surrounding the lesion, and a shift in the distribution of morphological and immunological phenotypes of these inflammatory cells. VEGF and PDGF delivered singly exacerbated secondary degeneration, increasing the size of the lesion cavity. These results demonstrate a novel therapeutic intervention for SCI, and reveal an unanticipated synergy for these growth factors whereby they modulated inflammatory processes and created a microenvironment conducive to axon preservation/sprouting.

Adaptive Neural Networks for Control of Movement Trajectories Invariant under Speed and Force Rescaling

This article describes two neural network modules that form part of an emerging theory of how adaptive control of goal-directed sensory-motor skills is achieved by humans and other animals. The Vector-Integration-To-Endpoint (VITE) model suggests how synchronous multi-joint trajectories are generated and performed at variable speeds. The Factorization-of-LEngth-and-TEnsion (FLETE) model suggests how outflow movement commands from a VITE model may be performed at variable force levels without a loss of positional accuracy. The invariance of positional control under speed and force rescaling sheds new light upon a familiar strategy of motor skill development: Skill learning begins with performance at low speed and low limb compliance and proceeds to higher speeds and compliances. The VITE model helps to explain many neural and behavioral data about trajectory formation, including data about neural coding within the posterior parietal cortex, motor cortex, and globus pallidus, and behavioral properties such as Woodworth's Law, Fitts Law, peak acceleration as a function of movement amplitude and duration, isotonic arm movement properties before and after arm-deafferentation, central error correction properties of isometric contractions, motor priming without overt action, velocity amplification during target switching, velocity profile invariance across different movement distances, changes in velocity profile asymmetry across different movement durations, staggered onset times for controlling linear trajectories with synchronous offset times, changes in the ratio of maximum to average velocity during discrete versus serial movements, and shared properties of arm and speech articulator movements. The FLETE model provides new insights into how spina-muscular circuits process variable forces without a loss of positional control. These results explicate the size principle of motor neuron recruitment, descending co-contractive compliance signals, Renshaw cells, Ia interneurons, fast automatic reactive control by ascending feedback from muscle spindles, slow adaptive predictive control via cerebellar learning using muscle spindle error signals to train adaptive movement gains, fractured somatotopy in the opponent organization of cerebellar learning, adaptive compensation for variable moment-arms, and force feedback from Golgi tendon organs. More generally, the models provide a computational rationale for the use of nonspecific control signals in volitional control, or "acts of will", and of efference copies and opponent processing in both reactive and adaptive motor control tasks.

Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. Clinical article

Object
Trigeminal neuralgia pain causes severe disability. Stereotactic radiosurgery is the least invasive surgical option for patients with trigeminal neuralgia. Since different medical and surgical options have different rates of pain relief and morbidity, it is important to evaluate longer-term outcomes.

Methods
The authors retrospectively reviewed outcomes in 503 medically refractory patients with trigeminal neuralgia who underwent Gamma Knife surgery (GKS). The median patient age was 72 years (range 26–95 years). Prior surgery had failed in 205 patients (43%). The GKS typically was performed using MR imaging guidance, a single 4-mm isocenter, and a maximum dose of 80 Gy.

Results
Patients were evaluated for up to 16 years after GKS; 107 patients had > 5 years of follow-up. Eighty-nine percent of patients achieved initial pain relief that was adequate or better, with or without medications (Barrow Neurological Institute [BNI] Scores I–IIIb). Significant pain relief (BNI Scores I–IIIa) was achieved in 73% at 1 year, 65% at 2 years, and 41% at 5 years. Including Score IIIb (pain adequately controlled with medication), a BNI score of I–IIIb was found in 80% at 1 year, 71% at 3 years, 46% at 5 years, and 30% at 10 years. A faster initial pain response including adequate and some pain relief was seen in patients with trigeminal neuralgia without additional symptoms, patients without prior surgery, and patients with a pain duration of = 3 years. One hundred ninety-three (43%) of 450 patients who achieved initial pain relief reported some recurrent pain 3–144 months after initial relief (median 50 months). Factors associated with earlier pain recurrence that failed to maintain adequate or some pain relief were trigeminal neuralgia with additional symptoms and = 3 prior failed surgical procedures. Fifty-three patients (10.5%) developed new or increased subjective facial paresthesias or numbness and 1 developed deafferentation pain; these symptoms resolved in 17 patients. Those who developed sensory loss had better long-term pain control (78% at 5 years).

Conclusions
Gamma Knife surgery proved to be safe and effective in the treatment of medically refractory trigeminal neuralgia and is of value for initial or recurrent pain management. Despite the goal of minimizing sensory loss with this procedure, some sensory loss may improve long-term outcomes. Pain relapse is amenable to additional GKS or another procedure.

The roles of the somatosensory cortices in the perception of noxious and innocuous stimuli

Résumé Les premières études électrophysiologiques et anatomiques ont établi le rôle crucial du cortex somatosensoriel primaire et secondaire (SI et SII) dans le traitement de l'information somatosensorielle. Toutefois, les récentes avancées en techniques d’imagerie cérébrale ont mis en question leur rôle dans la perception somatosensorielle. La réorganisation du cortex somatosensoriel est un phénomène qui a été proposé comme cause de la douleur du membre fantôme chez les individus amputés. Comme la plupart des études se sont concentrées sur le rôle du SI, une étude plus approfondie est nécessaire. La présente série d'expériences implique une exploration du rôle des régions somatosensorielles dans la perception des stimuli douleureux et non-douleureux chez des volontaires sains et patients avec des douleurs de membre fantôme. La première étude expérimentale présentée dans le chapitre 3 est une méta-analyse des études de neuro-imagerie employant des stimuli nociceptifs chez des volontaires sains. En comparaison aux précédentes, la présente étude permet la génération de cartes quantitatives probabilistes permettant la localisation des régions activées en réponse à des stimuli nociceptifs. Le rôle du cortex somatosensoriel dans la perception consciente de stimuli chauds a été étudié dans le chapitre 4 grâce à une étude d'imagerie par résonance magnétique fonctionnelle, dans laquelle des stimuli thermiques douloureux et non-douloureux ont été administrés de manière contrebalancée. Grâce à cette procédure, la perception de la chaleur fut atténuée par les stimuli douloureux, ce qui permit la comparaison des stimuli consciemment perçus avec ceux qui ne le furent pas. Les résultats ont montrés que les stimulations chaudes perçues ont engendré l’activation de l’aire SI controlatérale, ainsi que de la région SII. Grâce à l’évaluation clinique de patients amputés présentant une altération de leurs perceptions somatosensorielles, il est également possible de dessiner un aperçu des régions corticales qui sous-tendent ces modifications perceptuelles. Dans le chapitre 5 nous avons émis l'hypothèse proposant que les sensations du membre fantôme représentent un corrélat perceptuel de la réorganisation somatotopique des représentations sensorielles corticales. En effet, la réorganisation des sensations peut donner des indices sur les régions impliquées dans la genèse des sensations référées. Ainsi, un protocole d’évaluation sensoriel a été administré à un groupe de patients affligés de douleur au niveau du membre fantôme. Les résultats ont montré que, contrairement aux études précédentes, les sensations diffèrent grandement selon le type et l'intensité des stimuli tactiles, sans évidence de la présence d’un modèle spatialement localisé. Toutefois, les résultats actuels suggèrent que les régions corticales à champs récepteurs bilatéraux présentent également des modifications en réponse à une déafférentation. Ces études présentent une nouvelle image des régions corticales impliquées dans la perception des stimuli somatosensoriels, lesquelles comprennent les aires SI et SII, ainsi que l'insula. Les résultats sont pertinents à notre compréhension des corrélats neurologiques de la perception somatosensorielle consciente.

Retinal removal up-regulates cannabinoid CB1 receptors in the chick optic tectum

The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration and neuro protection. The aim of this study was to evaluate the effects of unilateral retinal ablation on the expression of the cannabinoid receptor subtype 1 (CB1) at both protein and mRNA levels in the optic tectum of the adult chick brain. After different survival times postlesion (2-30 days), the chick brains were subjected to immunohistochemical, immunoblotting, and real-time PCR procedures to evaluate CB1 expression. TUNEL and Fluoro-Jade B were used to verify the possible occurrence of cell death, and immunostaining for the microtubule-associated protein MAP-2 was performed to verify possible dendritic remodeling after lesions. No cell death could be observed in the deafferented tectum, at least up to 30 days postlesion, although Fluoro-Jade B could reveal degenerating axons and terminals. Retinal ablation seems to generate an increase of CB1 protein in the optic tectum and other retinorecipient visual areas, which paralleled an increase in MAP-2 staining. On the other hand, CB, mRNA levels were not changed after retinal ablation. Our results reveal that CB, expression in visual structures of the adult chick brain may be negatively regulated by the retinal innervation. The increase of CB1 receptor expression observed after retinal removal indicates that these receptors are not presynaptic in retinal axons projecting to the tectum and suggests a role of the cannabinoid system in plasticity processes ensuing after lesions. (c) 2008 Wiley-Liss, Inc.

REACTIVE OXYGEN SPECIES AND THE STRUCTURAL REMODELING OF THE VISUAL SYSTEM AFTER OCULAR ENUCLEATION

Redox processes associated with controlled generation of reactive oxygen species (ROS) by NADPH oxidase (Nox) add an essential level of regulation to signaling pathways underlying physiological processes. We evaluated the ROS generation in the main visual relays of the mammalian brain, namely the superior colliculus (SC) and the dorsal lateral geniculate nucleus (DLG), after ocular enucleation in adult rats. Dihydroethidium (DHE) oxidation revealed increased ROS generation in SC and DLG between 1 and 30 days postlesion. ROS generation was decreased by the Nox inhibitors diphenyleneiodonium chloride (DPI) and apocynin. Real-time PCR results revealed that Nox 2 was upregulated in both retinorecipient structures after deafferentation, whereas Nox 1 and Nox 4 were upregulated only in the SC. To evaluate the role of ROS in structural remodeling after the lesions, apocynin was given to enucleated rats and immunohistochemistry was conducted for markers of neuronal remodeling into SC and DLG. Immunohistochemical data showed that ocular enucleation produces an increase of neurofilament and microtubule-associated protein-2 immunostaining in both SC and DLG, which was markedly attenuated by apocynin treatment. Taken together, the findings of the present study suggest a novel role for Nox-induced ROS signaling in mediating neuronal remodeling in visual areas after ocular enucleation. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Residual function, spontaneous reorganisation and treatment plasticity in homonymous visual field defects

This thesis will focus on the residual function and visual and attentional deficits in human patients, which accompany damage to the visual cortex or its thalamic afferents, and plastic changes, which follow it. In particular, I will focus on homonymous visual field defects, which comprise a broad set of central disorders of vision. I will present experimental evidence that when the primary visual pathway is completely damaged, the only signal that can be implicitly processed via subcortical visual networks is fear. I will also present data showing that in a patient with relative deafferentation of visual cortex, changes in the spatial tuning and response gain of the contralesional and ipsilesional cortex are observed, which are accompanied by changes in functional connectivity with regions belonging to the dorsal attentional network and the default mode network. I will also discuss how cortical plasticity might be harnessed to improve recovery through novel treatments. Moreover, I will show how treatment interventions aimed at recruiting spared subcortical pathway supporting multisensory orienting can drive network level change.

Rapid Facilitation of Ultrasound Production and Lordosis in Female Hamsters by Horizontal Cuts Between the Septum and Preoptic Area

Horizontal cuts between the septum and preoptic area (anterior roof deafferentation, or ARD) dramatically affect sexual behavior, and in ways that could explain a variety of differences across behavioral categories (precopulatory, copulatory), species, and the sexes. Yet little is known about how these effects develop. Such information would be useful generally and could be pivotal in clarifying the mechanism for ultrasonic vocalization in female hamsters. Ultrasounds serve these animals as precopulatory signals that can attract males and help initiate mating. Their rates can be increased by either ARD or lesions of the ventromedial hypothalamus (VMN). If these effects are independent, they would require a mechanism that includes multiple structures and pathways within the forebrain and hypothalamus. However, it currently is not clear if they are independent: VMN lesions could affect vocalization by causing incidental damage to the same fibers targeted by ARD. Fortunately, past studies of VMN lesions have described a response with a very distinctive time course. This raises the possibility of assessing the independence of the two lesion effects by describing just the development of the response to ARD. To accomplish this, female hamsters were observed for levels of ultrasound production and lordosis before and after control surgery or ARD. As expected, both behaviors were facilitated by these cuts. Further, these effects began to appear by two days after surgery and were fully developed by six days. These results extend previous descriptions of the ARD effect by describing its development and time course. In turn, the rapid responses to ARD suggest that these cuts trigger disinhibitory changes in pathways that differ from those affected by VMN lesions. 2013

Restoring tactile awareness through the rubber hand illusion in cervical spinal cord injury

BACKGROUND Bodily sensations are an important component of corporeal awareness. Spinal cord injury can leave affected body parts insentient and unmoving, leading to specific disturbances in the mental representation of one's own body and the sense of self. OBJECTIVE Here, we explored how illusions induced by multisensory stimulation influence immediate sensory signals and tactile awareness in patients with spinal cord injuries. METHODS The rubber hand illusion paradigm was applied to 2 patients with chronic and complete spinal cord injury of the sixth cervical spine, with severe somatosensory impairments in 2 of 5 fingers. RESULTS Both patients experienced a strong illusion of ownership of the rubber hand during synchronous, but not asynchronous, stroking. They also, spontaneously reported basic tactile sensations in their previously numb fingers. Tactile awareness from seeing the rubber hand was enhanced by progressively increasing the stimulation duration. CONCLUSIONS Multisensory illusions directly and specifically modulate the reemergence of sensory memories and enhance tactile sensation, despite (or as a result of) prior deafferentation. When sensory inputs are lost, and are later illusorily regained, the brain updates a coherent body image even several years after the body has become permanently unable to feel. This particular example of neural plasticity represents a significant opportunity to strengthen the sense of the self and the feelings of embodiment in patients with spinal cord injury.

Immediate and simultaneous sensory reorganization at cortical and subcortical levels of the somatosensory system

The occurrence of cortical plasticity during adulthood has been demonstrated using many experimental paradigms. Whether this phenomenon is generated exclusively by changes in intrinsic cortical circuitry, or whether it involves concomitant cortical and subcortical reorganization, remains controversial. Here, we addressed this issue by simultaneously recording the extracellular activity of up to 135 neurons in the primary somatosensory cortex, ventral posterior medial nucleus of the thalamus, and trigeminal brainstem complex of adult rats, before and after a reversible sensory deactivation was produced by subcutaneous injections of lidocaine. Following the onset of the deactivation, immediate and simultaneous sensory reorganization was observed at all levels of the somatosensory system. No statistical difference was observed when the overall spatial extent of the cortical (9.1 ± 1.2 whiskers, mean ± SE) and the thalamic (6.1 ± 1.6 whiskers) reorganization was compared. Likewise, no significant difference was found in the percentage of cortical (71.1 ± 5.2%) and thalamic (66.4 ± 10.7%) neurons exhibiting unmasked sensory responses. Although unmasked cortical responses occurred at significantly higher latencies (19.6 ± 0.3 ms, mean ± SE) than thalamic responses (13.1 ± 0.6 ms), variations in neuronal latency induced by the sensory deafferentation occurred as often in the thalamus as in the cortex. These data clearly demonstrate that peripheral sensory deafferentation triggers a system-wide reorganization, and strongly suggest that the spatiotemporal attributes of cortical plasticity are paralleled by subcortical reorganization.

Progressive entorhinal cortex lesions accelerate hippocampal sprouting and spare spatial memory in rats

Accelerating hippocampal sprouting by making unilateral progressive lesions of the entorhinal cortex spared the spatial memory of rats tested for retention of a learned alternation task. Subsequent transection of the sprouted crossed temporodentate pathway (CTD), as well as a simultaneous CTD transection and progressive entorhinal lesion, produced a persistent deficit on the memory task. These results suggest that CTD sprouting, which is homologous to the original perforant path input to the dentate gyrus of the hippocampus, is behaviorally significant and can ameliorate at least some of the memory deficits associated with hippocampal deafferentation.

Olfactory marker protein (OMP) gene deletion causes altered physiological activity of olfactory sensory neurons.

Olfactory marker protein (OMP) is an abundant, phylogentically conserved, cytoplasmic protein of unknown function expressed almost exclusively in mature olfactory sensory neurons. To address its function, we generated OMP-deficient mice by gene targeting in embryonic stem cells. We report that these OMP-null mice are compromised in their ability to respond to odor stimull, providing insight to OMP function. The maximal electroolfactogram response of the olfactory neuroepithelium to several odorants was 20-40% smaller in the mutants compared with controls. In addition, the onset and recovery kinetics following isoamyl acetate stimulation are prolonged in the null mice. Furthermore, the ability of the mutants to respond to the second odor pulse of a pair is impaired, over a range of concentrations, compared with controls. These results imply that neural activity directed toward the olfactory bulb is also reduced. The bulbar phenotype observed in the OMP-null mouse is consistent with this hypothesis. Bulbar activity of tyrosine hydroxylase, the rate limiting enzyme of catecholamine biosynthesis, and content of the neuropeptide cholecystokinin are reduced by 65% and 50%, respectively. This similarity to postsynaptic changes in gene expression induced by peripheral olfactory deafferentation or naris blockade confirms that functional neural activity is reduced in both the olfactory neuroepithelium and the olfactory nerve projection to the bulb in the OMP-null mouse. These observations provide strong support for the conclusion that OMP is a novel modulatory component of the odor detection/signal transduction cascade.

Topographic plasticity in primary visual cortex is mediated by local corticocortical connections

The placement of monocular laser lesions in the adult cat retina produces a lesion projection zone (LPZ) in primary visual cortex (V1) in which the majority of neurons have a normally located receptive field (RF) for stimulation of the intact eye and an ectopically located RF ( displaced to intact retina at the edge of the lesion) for stimulation of the lesioned eye. Animals that had such lesions for 14 - 85 d were studied under halothane and nitrous oxide anesthesia with conventional neurophysiological recording techniques and stimulation of moving light bars. Previous work suggested that a candidate source of input, which could account for the development of the ectopic RFs, was long-range horizontal connections within V1. The critical contribution of such input was examined by placing a pipette containing the neurotoxin kainic acid at a site in the normal V1 visual representation that overlapped with the ectopic RF recorded at a site within the LPZ. Continuation of well defined responses to stimulation of the intact eye served as a control against direct effects of the kainic acid at the LPZ recording site. In six of seven cases examined, kainic acid deactivation of neurons at the injection site blocked responsiveness to lesioned-eye stimulation at the ectopic RF for the LPZ recording site. We therefore conclude that long-range horizontal projections contribute to the dominant input underlying the capacity for retinal lesion-induced plasticity in V1.