K Index in cerebrospinal fluid: a valid tool in multiple sclerosis diagnosis

Detection of oligoclonal IgG bands in cerebrospinal fluid by isoelectrocfocusing and immunodetection is the current gold standard to detect an inflammatory process in the central nervous system. It has been proposed that the presence of free light chains (FLCs) in CSF was associated with recent demyelination activity in MS and might be used as a prognosis marker. Our study’s objective is assessing the diagnostic accuracy of a new highly sensitive latex-enhanced nephelometric assay for k free light chain (kFLC) determination in CSF/serum as an alternative to traditional tests and its clinical application. Methods. kFLCs were measured in CSF/serum pairs from 80 patients by the use of a new highly sensitive latex-enhanced nephelometric automated immunoassay for detection of immunoglobulin FLC. The eighty patients were split into three groups according to the neurological diagnosis. In this study we confirm even more the use of the k Index as a diagnostic aid in multiple sclerosis. Results. kFLC Index seems to be more accurate parameter respect the determination of oligoclonal immunoglobulin bands (OCBs). We recalculate the K Index sensitivity and specificity respect the precedent published result. Two patients previously diagnosed with leukoencephalopathy have gone to group 3 as confirmed the diagnosis of MS. Conclusions. These new data reinforce even more the use of the k Index to diagnose MS in comparison to classical methods and to the reference method, the OCBs

Reinforcement learning in populations of spiking neurons

Population coding is widely regarded as a key mechanism for achieving reliable behavioral responses in the face of neuronal variability. But in standard reinforcement learning a flip-side becomes apparent. Learning slows down with increasing population size since the global reinforcement becomes less and less related to the performance of any single neuron. We show that, in contrast, learning speeds up with increasing population size if feedback about the populationresponse modulates synaptic plasticity in addition to global reinforcement. The two feedback signals (reinforcement and population-response signal) can be encoded by ambient neurotransmitter concentrations which vary slowly, yielding a fully online plasticity rule where the learning of a stimulus is interleaved with the processing of the subsequent one. The assumption of a single additional feedback mechanism therefore reconciles biological plausibility with efficient learning

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains

Cerebellar control of cortico-striatal LTD

Purpose: Recent anatomical studies showed the presence of cerebellar and basal ganglia connections. It is thus conceivable that the cerebellum may influence the striatal synaptic transmission in general, and synaptic plasticity in particular. Methods: In the present neurophysiological investigation in brain slices, we studied striatal long-term depression (LTD), a crucial form of synaptic plasticity involved in motor learning after cerebellar lesions in rats. Results: Striatal LTD was fully abolished in the left striatum of rats with right hemicerebellectomy recorded 3 and 7 days following surgery, when the motor deficits were at their peak. Fifteen days after the hemicerebellectomy, rats had partially compensated their motor deficits and high-frequency stimulation of excitatory synapses in the left striatum was able to induce a stable LTD. Striatal plasticity was conversely normal ipsilaterally to cerebellar lesions, as well as in the right and left striatum of sham-operated animals. Conclusions: These data show that the cerebellum controls striatal synaptic plasticity, supporting the notion that the two structures operate in conjunction during motor learning

Dopamine-modulated dynamic cell assemblies generated by the GABAergic striatal microcircuit

The striatum, the principal input structure of the basal ganglia, is crucial to both motor control and learning. It receives convergent input from all over the neocortex, hippocampal formation, amygdala and thalamus, and is the primary recipient of dopamine in the brain. Within the striatum is a GABAergic microcircuit that acts upon these inputs, formed by the dominant medium-spiny projection neurons (MSNs) and fast-spiking interneurons (FSIs). There has been little progress in understanding the computations it performs, hampered by the non-laminar structure that prevents identification of a repeating canonical microcircuit. We here begin the identification of potential dynamically-defined computational elements within the striatum. We construct a new three-dimensional model of the striatal microcircuit's connectivity, and instantiate this with our dopamine-modulated neuron models of the MSNs and FSIs. A new model of gap junctions between the FSIs is introduced and tuned to experimental data. We introduce a novel multiple spike-train analysis method, and apply this to the outputs of the model to find groups of synchronised neurons at multiple time-scales. We find that, with realistic in vivo background input, small assemblies of synchronised MSNs spontaneously appear, consistent with experimental observations, and that the number of assemblies and the time-scale of synchronisation is strongly dependent on the simulated concentration of dopamine. We also show that feed-forward inhibition from the FSIs counter-intuitively increases the firing rate of the MSNs. Such small cell assemblies forming spontaneously only in the absence of dopamine may contribute to motor control problems seen in humans and animals following a loss of dopamine cells. (C) 2009 Elsevier Ltd. All rights reserved

Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis

Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS

The Link Among Neurological Diseases: Extracellular Vesicles as a Possible Brain Injury Footprint

Extracellular vesicles (EVs), referred as membranous vesicles released into body fluids from all cell types, represent a novel model to explain some aspects of the inter-cellular cross talk. It has been demonstrated that the EVs modify the phenotype of target cells, acting through a large spectrum of mechanisms. In the central nervous system, the EVs are responsible of the wide range of physiological processes required for normal brain function and neuronal support, such as immune signaling, cellular proliferation, differentiation, and senescence. Growing evidences link the EV functions to the pathogenic machinery of the neurological diseases, contributing to the disease progression and spreading. Extracellular vesicles are involved in the brain injury by multimodal ways; they propagate inflammation across the blood brain barrier (BBB), mediate neuroprotection and modulate regenerative processes. For these reasons, extracellular vesicles represent a promising biomarker in neurological disorders as well as an interesting starting point for the development of novel therapeutic strategies. Herein, we review the role of the EVs in the pathogenesis of neurological disease, discussing their potential clinical applications

Quality of life, depression and fatigue in mildly disabled patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: 3-year results from the COGIMUS (COGnitive Impairment in MUltiple Sclerosis) study.

BACKGROUND: The precise relationships among quality of life, depression, fatigue and cognitive impairment in multiple sclerosis (MS) are complex and poorly understood. OBJECTIVE: To assess the effects of subcutaneous interferon beta-1a on quality of life, depression and fatigue over 3 years in the COGIMUS study, and to examine the relationship between these outcomes and baseline cognitive status. METHODS: COGIMUS was an observational 3-year trial assessing cognitive function in 459 patients with relapsing-remitting MS treated with subcutaneous interferon beta-1a. RESULTS: In total, 331 patients completed the study (168 received interferon beta-1a, 44 µg subcutaneously three times weekly, and 163 received interferon beta-1a, 22 µg subcutaneously three times weekly). Mean MS Quality of Life-54 (MSQoL-54) composite scores did not change over time. There were no significant differences between groups in MSQoL-54 composite scores when patients were grouped by treatment dose and baseline cognitive status. Mean (standard deviation) Hamilton Depression Rating Scale score decreased from 6.8 (4.9) at baseline to 5.8 (5.9) at year 3. Mean total Fatigue Impact Scale scores were low (<30) at all time points. CONCLUSION: Quality of life, depression and fatigue remained largely stable over 3 years; no effects of treatment dose or baseline cognitive status were found

Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

Investigation of fennel protein extracts by shot-gun Fourier transform ion cyclotron resonance mass spectrometry

A rapid shot-gun method by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is proposed for the characterization of fennel proteins. After enzymatic digestion with trypsin, few microliters of extract were analyzed by direct infusion in positive ion mode. A custom-made non-redundant fennel-specific proteome database was derived from the well-known NCBI database; additional proteins belonging to recognized allergenic sources (celery, carrot, parsley, birch, and mugwort) were also included in our database, since patients hypersensitive to these plants could also suffer from fennel allergy. The peptide sequence of each protein from that derived list was theoretically sequenced to produce calculated m/z lists of possible m/z ions after tryptic digestions. Then, by using a home-made Matlab algorithm, those lists were matched with the experimental FT-ICR mass spectrum of the fennel peptide mixture. Finally, Peptide Mass Fingerprint searches confirmed the presence of the matched proteins inside the fennel extract with a total of 70 proteins (61 fennel specific and 9 allergenic proteins)