Multisession anodal epidural direct current stimulation of the auditory cortex delays the progression of presbycusis in the Wistar rat.

Presbycusis or age-related hearing loss (ARHL) is one of the most prevalent chronic health problems facing aging populations. Along the auditory pathway, the stations involved in transmission and processing, function as a system of interconnected feedback loops. Regulating hierarchically auditory processing, auditory cortex (AC) neuromodulation can, accordingly, activate both peripheral and central plasticity after hearing loss. However, previous ARHL-prevention interventions have mainly focused on preserving the structural and functional integrity of the inner ear, overlooking the central auditory system. In this study, using an animal model of spontaneous ARHL, we aim at assessing the effects of multisession epidural direct current stimulation of the AC through stereotaxic implantation of a 1-mm silver ball anode in Wistar rats. Consisting of 7 sessions (0.1 mA/10 min), on alternate days, in awake animals, our stimulation protocol was applied at the onset of hearing loss (threshold shift detection at 16 months). Click- and pure-tone auditory brainstem responses (ABRs) were analyzed in two animal groups, namely electrically stimulated (ES) and non-stimulated (NES) sham controls, comparing recordings at 18 months of age. At 18 months, NES animals showed significantly increased threshold shifts, decreased wave amplitudes, and increased wave latencies after click and tonal ABRs, reflecting a significant, spontaneous ARHL evolution. Conversely, in ES animals, no significant differences were detected in any of these parameters when comparing 16 and 18 months ABRs, indicating a delay in ARHL progression. Electrode placement in the auditory cortex was accurate, and the stimulation did not cause significant damage, as shown by the limited presence of superficial reactive microglial cells after IBA1 immunostaining. In conclusion, multisession DC stimulation of the AC has a protective effect on auditory function, delaying the progression of presbycusis.

De Onofre Gil a Carlos Castilla del Pino: scientia, sapientia et infantia / From Onofre Gil to Carlos Castilla del Pino: Scientia, Sapientia et Infantia

Aunque más breve que su producción ensayística y psicopatológica, la obra literaria de Carlos Castilla del Pino resulta de gran interés por la calidad de su escritura y como memoria privilegiada de un tiempo y de un país, así como por el empeño del autor por crear un discurso “personal”, lúcido, veraz, racional y bello que no solo estuviese al servicio de su propio personaje, sino que le ayudase a constituirse como sujeto con scientia, sapientia e infantia. En este sentido, confrontamos sus dos libros de memo-rias (Pretérito imperfecto y La casa del olivo) con su novela Discurso de Onofre: obras en principio dispares pero que –curiosamente y de forma privilegiada– dan cuenta del continuum y de los sobresaltos, de los riesgos y renuncias, que suponen la aventura de vivir con la sabiduría que emana del saber estar en el mundo; o sea, de una actitud grácil ante las dificultades inherentes al hecho de vivir en la que se anuda el mayor o menor conocimiento que el autor ha ido adquiriendo a lo largo de su vida con la vivencia gozosa del sentido de su propia existencia y con la capacidad para entender y disfrutar lo que es bueno, justo y bello. (AU)

Although shorter in number than his essays and works on psychopathology, Car-los Castilla del Pino ́s literary work is of great interest due to the quality of his writing and as a privileged memory of a time and a country. It shows his effort to create a personal, lucid, truthful, rational and beautiful discourse that was not only at the service of his own charac-ter, but also helped him to establish himself as a subject with scientia, sapientia and infantia. In this sense, we confront his two memoirs (Pretérito imperfecto and La casa del olivo) with his novel Discurso de Onofre: works that are dissimilar in principle, but that -curiously and in a privileged way- give an account of the continuum and the shocks, the risks and renun-ciations, that the adventure of living with the wisdom that emanates from knowing how to be in the world involves. In these works, the greater or lesser knowledge that the author has acquired throughout his life is tied with the joyful experience of the meaning of his own existence, and with the capacity to understand and enjoy what is good, fair and beautiful. (AU)

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression.

Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology. Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1 and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies.

Aerobiología de polen del olivo en las ciudades de Tacna y Arica y su relación con las enfermedades alérgicas respiratorias / Olive pollen aerobiology in Tacna and Arica cities and it is relation with the allergic respiratory diseases

Medir la concentración del polen en la atmósfera se ha convertido en objeto de interés a nivel mundial debido al aumento de las enfermedades alérgicas, ya que en muchas personas es causa de polinosis. Objetivos: se centró en la elaboración de un calendario de polen del olivo, basado en medir su concentración en las ciudades de Tacna (desde 2015 al 2018) y Arica (periodo 2018), y determinar la prevalencia de resultados positivos para extracto alergénico de polen del olivo en pacientes con síntomas de rinitis y/o asma provenientes de las ciudades de Tacna y Arica (periodo 2015-2018). Métodos: Se midió la concentración de polen, mediante el método volumétrico tipo Hirst, según estándares establecidos por el comité de aerobiología de la Sociedad Española de Alergología e Inmunología Clínica (SEAIC). Se incluyó una muestra total de 350 sujetos con síntomas respiratorios (200 de Tacna y 150 de Arica). Resultados: En Tacna, en 2015, 2016, 2017 y 2018, la concentración máxima de polen de olivo fue de 246 granos/m3 ; 110 granos/m3 ; 78 granos/ m3 y 688 granos/m3 respectivamente. En Arica en 2018, la concentración máxima de polen del olivo fue de 318 granos/ m3 . Se encontró que un 34% (68/200) y un 28% (42/150) de sujetos con síntomas respiratorios estaban sensibilizados u obtuvieron pruebas positivas al extracto de polen del olivo en sujetos de las ciudades de Tacna y Arica respectivamente. Conclusión: En ambas ciudades las concentraciones máximas de polen del olivo se encontraron principalmente entre los meses de septiembre a noviembre, siendo octubre el mes de mayores conteos. Se identificó sujetos alérgicos por test cutáneo al polen del olivo en las ciudades de Tacna y Arica.

The measurement of the concentration of pollen in the atmosphere has become an object of interest worldwide for the increase of allergy diseases, since in many people it is the cause of pollinosis. Objectives: focused on the elaboration of a calendar of olive tree pollen based on the measurement of the pollen concentration in Tacna (since 2015 to 2018) and Arica (period 2018) cities, and to determine the prevalence of positive results for allergenic extract of olive pollen in patients with symptoms of rhinitis and / or asthma, who came from Tacna and Arica cities (period 2015 to 2018). Methods. The pollen concentration was measured using the volumetric method according to standards established by the Aerobiology Committee of the Spanish Society of Allergology and Clinical Immunology (SEAIC), we included 350 subjects (200 from Tacna and 150 from Arica). Results: In Tacna, in 2015, 2016, 2017 and 2018, the maximum concentration of olive pollen was 246 grains/m3; 110 grains/m3; 78 grains/m3 and 688 grains/m3 respectively. In Arica in 2018, the maximum concentration of olive pollen was 318 grains/m3. We found 34% (68/200) and 28% (42/150) were sensitized or results positive test to the olive pollen extract in subjects with respiratory symptoms from Tacna and Arica cities respectively. Conclusion: The olive pollen in the atmosphere of Tacna and Arica is mainly concentrated in the months of September to November, being October the month with higher count. Allergic subjects were identified by skin test to olive pollen in Tacna and Arica cities.

Sleep deprivation directly following eyeblink-conditioning impairs memory consolidation.

The relation between sleep and different forms of memory formation continues to be a relevant topic in our daily life. Sleep has been found to affect cerebellum-dependent procedural memory formation, but it remains to be elucidated to what extent the level of sleep deprivation directly after motor training also influences our ability to store and retrieve memories. Here, we studied the effect of disturbed sleep in mice during two different time-windows, one covering the first four hours following eyeblink conditioning (EBC) and another window following the next period of four hours. Compared to control mice with sleep ad libitum, the percentage of conditioned responses and their amplitude were impaired when mice were deprived of sleep directly after conditioning. This impairment was still significant when the learned EBC responses were extinguished and later reacquired. However, consolidation of eyeblink responses was not affected when mice were deprived later than four hours after acquisition, not even when tested during a different day-night cycle for control. Moreover, mice that slept longer directly following EBC showed a tendency for more conditioned responses. Our data indicate that consolidation of motor memories can benefit from sleep directly following memory formation.

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism.

Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

Does the Efferent Auditory System Have a Role in Children with Specific Learning Disabilities?

OBJECTIVE: This study aimed to compare the baseline transient otoacoustic emission (t-OAE) amplitudes and medial olivo-cochlear (MOC) efferent activity in children with specific learning disability (SLD) and children with normal development. METHODS: The study was conducted in two groups. The patient group included 30 children aged 6 to 10 years and diagnosed with SLD, and the control group included 30 children in the same age range without SLD. The patient group included eight males and 22 females, and the control group included 14 females and 16 males. t-OAE and contralateral suppression test were performed in both groups. RESULTS: In the first t-OAE measurements, a statistically significant difference was observed between the patient and the control group at frequencies of 1400, 2000, 2800, and 4000 Hz, but no such difference was observed at 1000 Hz frequency. In the control group, significantly better emission amplitudes were observed. No differences were found at any frequency between the patient and the control groups after suppression. When the subjects in the two groups were compared among themselves, there was a statistically significant difference between the before and after suppression scores in the patient group except at 4000 Hz. Likewise, an important difference was also observed in all frequencies in the control group. CONCLUSION: This study shows that suppression effects of t-OAE on children diagnosed with SLD and children with no SDL are not significantly different.

Variability and directionality of inferior olive neuron dendrites revealed by detailed 3D characterization of an extensive morphological library.

The inferior olive (IO) is an evolutionarily conserved brain stem structure and its output activity plays a major role in the cerebellar computation necessary for controlling the temporal accuracy of motor behavior. The precise timing and synchronization of IO network activity has been attributed to the dendro-dendritic gap junctions mediating electrical coupling within the IO nucleus. Thus, the dendritic morphology and spatial arrangement of IO neurons governs how synchronized activity emerges in this nucleus. To date, IO neuron structural properties have been characterized in few studies and with small numbers of neurons; these investigations have described IO neurons as belonging to two morphologically distinct types, "curly" and "straight". In this work we collect a large number of individual IO neuron morphologies visualized using different labeling techniques and present a thorough examination of their morphological properties and spatial arrangement within the olivary neuropil. Our results show that the extensive heterogeneity in IO neuron dendritic morphologies occupies a continuous range between the classically described "curly" and "straight" types, and that this continuum is well represented by a relatively simple measure of "straightness". Furthermore, we find that IO neuron dendritic trees are often directionally oriented. Combined with an examination of cell body density distributions and dendritic orientation of adjacent IO neurons, our results suggest that the IO network may be organized into groups of densely coupled neurons interspersed with areas of weaker coupling.

Assessment of the efferent auditory system in children with suspected auditory processing disorder: the Middle ear muscle reflex and contralateral inhibition of OAEs.

OBJECTIVE: To determine whether children aged 7 to 12 years with listening difficulties show objective evidence for efferent auditory function based on measurements of medial olivo-cochlear and middle ear muscle reflexes. DESIGN: Click-evoked otoacoustic emissions recorded with and without contralateral broadband noise and ipsilateral and contralateral tonal (1000, 2000 Hz) middle ear muscle reflex thresholds were examined. STUDY SAMPLE: 29 children diagnosed with suspected auditory processing disorder (APD) and a control group of 34 typically developing children participated in this study. RESULTS: Children with suspected APD had poorer performance on auditory processing tests than the control group. Middle ear muscle reflex thresholds were significantly higher at 2000 Hz in the suspected APD group for contralateral stimulation. MOC inhibition effects did not differ between APD and control groups. CONCLUSIONS: This research supports earlier studies showing altered acoustic reflexes in children with APD. No group differences were found for the MOC reflex measures, consistent with some earlier studies in children with APD.

Autonomic function testing in spinocerebellar ataxia type 2.

PURPOSE: To assess whether autonomic failure belongs to the clinical spectrum of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant genetic disorder showing progressive cerebellar and brainstem dysfunction. METHODS: We evaluated cardiovascular autonomic function in 8 patients with SCA2 and 16 age- and gender-matched healthy controls. Other autonomic domains were examined through standardized questionnaires and by testing the skin sympathetic reflex. RESULTS: Patients with SCA2 showed normal responses to cardiovascular autonomic function tests, with the exception of lower baroreflex sensitivity upon standing compared to controls. In questionnaires, 7 out of 8 patients reported bladder disturbances, while 3 out of 6 tested patients had no skin sympathetic reflex. CONCLUSIONS: We did not observe clinically overt cardiovascular autonomic failure in patients with SCA2. Other autonomic domains (i.e., bladder and sudomotor function) may be affected in the disease.

Inferior Olivary TMEM16B Mediates Cerebellar Motor Learning.

Ca2+-activated ion channels shape membrane excitability and Ca2+ dynamics in response to cytoplasmic Ca2+ elevation. Compared to the Ca2+-activated K+ channels, known as BK and SK channels, the physiological importance of Ca2+-activated Cl- channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca2+ influx through the dendritic high-threshold voltage-gated Ca2+ channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability.

Differences in the suppression of distortion product otoacoustic emissions by contralateral white noise between patients with acute or chronic tinnitus.

OBJECTIVE: The mechanisms underlying the shift from acute tinnitus to chronic remain obscure. An association between tinnitus and medial olivocochlear bundle (MOCB) reflex dysfunction has been hypothesised by several studies. The differences between participants with acute and chronic tinnitus have not yet been investigated. DESIGN: Participants were examined with distortion product otoacoustic emissions (DPOAEs) suppression elicited by contralateral white noise. They were compared in terms of frequency regions with non-recordable DPOAEs, suppression amplitudes and the presence of DPOAE enhancement. STUDY SAMPLE: Eighteen participants with acute tinnitus, 40 age-matched adults with chronic tinnitus and 17 controls were included. All participants (aged 34.7 ± 9.6years; mean ± Standard deviation) had normal hearing. Tinnitus was bilateral in 22 participants and unilateral in 36. RESULTS: Ears with chronic tinnitus presented significantly lower DPOAE suppression amplitudes than ears with acute tinnitus (p < 0.0001). Both acute and chronic tinnitus ears present a high prevalence of enhancement, significantly different from controls (p < 0.0001, p = 0.0002, respectively). Non-recordable DPOAEs were significantly more frequent in the chronic than in the acute tinnitus and control groups (p < 0.0001). CONCLUSIONS: The differences between study groups indicate that when tinnitus becomes chronic, DPOAEs suppression presents changes that might reveal corresponding steps in tinnitus pathophysiology. Treatment implications are discussed.

Behavioral correlates of complex spike synchrony in cerebellar microzones.

The olivo-cerebellar system is crucial for smooth and well timed execution of movements based on sensory and proprioceptive cues. The inferior olive (IO) plays a pivotal role in this process by synchronizing its activity across neurons internally through connexin36 gap junctions and providing a timing and/or learning signal to the cerebellum. Even though synchrony achieved through electrical coupling in IO cells is generally thought to be important in timing motor output, a direct relation between timing of movement and synchrony of olivary discharges has never been demonstrated within functional microcomplexes using transgenics. Here we combined in vivo, two-photon calcium imaging of complex spikes in microcomplexes of Purkinje cell (PC) dendrites with high-speed filming of tail, trunk, and limb movements in awake wild-type and connexin36-deficient mice. In wild types at rest, functional clusters of PCs were poorly defined with synchrony correlations that were relatively small and spatially limited to mediolateral distances of ∼50 µm, whereas during locomotion synchrony of the same PCs increased in strength and extended over distances spanning multiple microzones that could be correlated to specific components of sharp and well bounded movements. Instead, connexin36-deficient mice exhibited prolonged and desynchronized complex spike activity within PC microcomplexes both at rest and during behavior. Importantly, the mutants also showed concomitant abnormalities in the execution of spinocerebellar reflexes, which were significantly slower and more gradual than in wild-type littermates, particularly following sensory perturbations. Our results highlight the importance of modulation of synchronous activity within and between cerebellar microcomplexes in on-line temporal processing of motor output.

Clusters of cerebellar Purkinje cells control their afferent climbing fiber discharge.

Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning.

Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation.

The cerebellum refines the accuracy and timing of motor performance. How it encodes information to perform these functions is a major topic of interest. We performed whole cell and extracellular recordings of Purkinje cells (PCs) and cerebellar nuclei neurons (CNs) in vivo, while activating PCs with light in transgenic mice. We show for the first time that graded activation of PCs translates into proportional CN inhibition and induces rebound activity in CNs, which is followed by graded motor contractions timed to the cessation of the stimulus. Moreover, activation of PC ensembles led to disinhibition of climbing fiber activity, which coincided with rebound activity in CNs. Our data indicate that cessation of concerted activity in ensembles of PCs can regulate both timing and strength of movements via control of rebound activity in CNs.

Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse.

Cerebellar cortex has an elaborate rostrocaudal organization comprised of numerous microzones. Purkinje cells (PCs) in the same microzone show synchronous activity of complex spikes (CSs) evoked by excitatory inputs from climbing fibers (CFs) that arise from neurons in the inferior olive (IO). The synchronous CS activity is considered to depend on electrical coupling among IO neurons and anatomical organization of the olivo-cerebellar projection. To determine how the CF-PC wiring contributes to the formation of microzone, we examined the synchronous CS activities between neighboring PCs in the glutamate receptor δ2 knockout (GluD2 KO) mouse in which exuberant surplus CFs make ectopic innervations onto distal dendrites of PCs. We performed in vivo two-photon calcium imaging for PC populations to detect CF inputs. Neighboring PCs in GluD2 KO mice showed higher synchrony of calcium transients than those in wild-type (control) mice. Moreover, the synchrony in GluD2 KO mice hardly declined with mediolateral separation between PCs up to ~200 µm, which was in marked contrast to the falloff of the synchrony in control mice. The enhanced synchrony was only partially affected by the blockade of gap junctional coupling. On the other hand, transverse CF collaterals in GluD2 KO mice extended beyond the border of microzone and formed locally clustered ectopic synapses onto dendrites of neighboring PCs. Furthermore, PCs in GluD2 KO mice exhibited clustered firing (Cf), the characteristic CF response that was not found in PCs of wild-type mice. Importantly, Cf was often associated with localized calcium transients in distal dendrites of PCs, which are likely to contribute to the enhanced synchrony of calcium signals in GluD2 KO mice. Thus, our results indicate that CF signals in GluD2 KO mice propagate across multiple microzones, and that proper formation of longitudinal olivo-cerebellar projection is essential for the spatiotemporal organization of CS activity in the cerebellum.

In and out of the loop: external and internal modulation of the olivo-cerebellar loop.

Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo-cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios.

The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties.

The reflexological view of brain function (Sherrington, 1906) has played a crucial role in defining both the nature of connectivity and the role of the synaptic interactions among neuronal circuits. One implicit assumption of this view, however, has been that CNS function is fundamentally driven by sensory input. This view was questioned as early as the beginning of the last century when a possible role for intrinsic activity in CNS function was proposed by Thomas Graham Brow (Brown, 1911, 1914). However, little progress was made in addressing intrinsic neuronal properties in vertebrates until the discovery of calcium conductances in vertebrate central neurons leading dendritic electroresponsiveness (Llinás and Hess, 1976; Llinás and Sugimori, 1980a,b) and subthreshold neuronal oscillation in mammalian inferior olive (IO) neurons (Llinás and Yarom, 1981a,b). This happened in parallel with a similar set of findings concerning invertebrate neuronal system (Marder and Bucher, 2001). The generalization into a more global view of intrinsic rhythmicity, at forebrain level, occurred initially with the demonstration that the thalamus has similar oscillatory properties (Llinás and Jahnsen, 1982) and the ionic properties responsible for some oscillatory activity were, in fact, similar to those in the IO (Jahnsen and Llinás, 1984; Llinás, 1988). Thus, lending support to the view that not only motricity, but cognitive properties, are organized as coherent oscillatory states (Pare et al., 1992; Singer, 1993; Hardcastle, 1997; Llinás et al., 1998; Varela et al., 2001).

Spontaneous Intracranial Epidural Hematoma Following Thoracolumbar Schwannoma Removal

We report a case of spontaneous intracranial epidural hematoma following the intraoperative course of a patient who had undergone surgical removal of a thoracolumbar schwannoma in olivo-ponto-cerebellar atrophy. To our knowledge there is no reported case in which the thoracolumbar schwannoma removal was followed by such a complication. Mechanical events leading to this complication are unclear. Abnormal results of a neurological examination in the early postoperative period should suggest this possibility.