Molecular evidence and clinical significance of herpesvirus coinfection in the central nervous system.

A total of 60 cerebrospinal fluid (CSF) specimens from patients manifesting symptoms resembling viral central nervous system (CNS) disease were examined for the presence of herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), cytomegalovirus, varicella-zoster virus, Borrelia burgdorferi, and Tropheryma whippelii DNA by PCR. Of 30 specimens which were selected on the basis of HSV DNA positivity, 2 were concomitantly positive for HHV-6 DNA and 1 was positive for EBV DNA. In the three specimens positive for more than one herpesvirus, amplicons generated with virus-specific primer sets hybridized specifically to the corresponding virus-specific probe. Sequence analysis of the two amplified DNA fragments demonstrated that they were derived from distinct herpesviruses. Of 22 patients with clinically diagnosed encephalitis, 2 of 3 patients coinfected with HSV and HHV-6 died, compared to 1 of 19 (5%) patients infected with only HSV. Of 30 CSF specimens that were negative for HSV DNA, EBV DNA was detected in one sample. These data indicated the presence of DNA specific for two distinct herpesviruses in the same CSF specimen, providing molecular evidence that coinfection with this group of viruses may occur in the CNS.     

Temporal dynamics of binocular disparity processing in the central visual pathway

To solve the stereo correspondence problem (i.e., find the matching features of a visual scene in both eyes), it is advantageous to combine information across spatial scales. The details of how this is accomplished are not clear. Psychophysical studies and mathematical models have suggested various types of interactions across spatial scale, including coarse to fine, fine to coarse, averaging, and population coding. In this study, we investigate dynamic changes in disparity tuning of simple and complex cells in the cat's striate cortex over a short time span. We find that disparity frequency increases and disparity ranges decrease while optimal disparity remains constant, and this conforms to a coarse-to-fine mechanism. We explore the origin of this mechanism by examining the frequency and size dynamics exhibited by binocular simple cells and neurons in the lateral geniculate nucleus (LGN). The results suggest a strong role for a feed-forward mechanism, which could originate in the retina. However, we find that the dynamic changes seen in the disparity range of simple cells cannot be predicted from their left and right eye monocular receptive field (RF) size changes. This discrepancy suggests the possibility of a dynamic nonlinearity or disparity specific feedback that alters tuning or a combination of both mechanisms.     

Information processing in the central nervous system during functional electrical stimulation

One of the most recent orthotic and therapeutical approaches to hemiplegia is functional electrical stimulation. It was observed that the electronic peroneal brace which is applied to hemiplegics with drop-foot, produces in some patients long-term effects which outlast the actual stimulation time. The paper proposes two models which explain the clinical observations and suggests further experiments in order to obtain more realistic models.     

Optimizing clinical monitoring of central nervous system involvement in SLE

Central Nervous System (CNS) involvement is a frequent SLE manifestation occurring in 15-75% of patients. However, diagnosis of CNS involvement is a difficult task and requires a careful clinical and laboratory assessment along with instrumental evaluation. In recent years major advances in neuroimaging techniques allowed a great improvement in our understanding of SLE pathogenesis. Anyway, since no single imaging technique covers all brain pathology and both inflammation and neurodegeneration contribute to SLE pathogenesis, it is very important to use a multimodality approach coupling a morphological with a functional imaging modality. In this setting, to date, conventional magnetic resonance imaging and single photon emission computed tomography are the most largely available and accessible techniques. Modern techniques such as perfusion weighted imaging, diffusion weighted imaging, magnetization transfer imaging and magnetic resonance spectroscopy provide useful information to assess brain tissue damage however, their clinical relevance in individual patients needs further evidence. In this review we would like to summarize what have we learned in the last few years about neuroimaging in NPSLE, what have been major advances in neuroimaging techniques and, finally, we would like to give some suggestions about what should be done in daily clinical practice to approach SLE patients with NP symptoms.     

Temporal factors in tactile spatial acuity: evidence for RA interference in fine spatial processing

We investigated the extent to which subjects' ability to perceive the fine spatial structure of a stimulus depends on its temporal properties (namely the frequency at which it vibrates). Subjects were presented with static or vibrating gratings that varied in spatial period (1-8 mm) and vibratory frequency (5-80 Hz) and judged the orientation of the gratings, presented either parallel or perpendicular to the long axis of the finger. We found that the grating orientation threshold (GOT)-the spatial period at which subjects can reliably discriminate the orientation of the grating-increased as the vibratory frequency of the gratings increased. As the spatial modulation of SA1 and RA afferent fibers has been found to be independent of vibratory frequency, the frequency dependence of spatial acuity cannot be attributed to changes in the quality of the peripheral signal. Furthermore, we found GOTs to be relatively independent of stimulus amplitude, so the low spatial acuity at high flutter frequencies does not appear to be due to an inadequacy in the strength of the afferent response at those frequencies. We hypothesized that the RA signal, the strength of which increases with vibratory frequency, interfered with the spatially modulated signal conveyed by SA1 fibers. Consistent with this hypothesis, we found that adapting RA afferent fibers improved spatial acuity, as gauged by GOTs, at the high flutter frequencies.     

Differential influences of exercise intensity on information processing in the central nervous system

The influence of exercise intensity on information processing in the central nervous system was investigated using P300 and no-go P300 event-related potentials. Twelve subjects (22–33 years) performed a go/no-go reaction time task in a control condition, and again after high-, medium-, and low-intensity pedaling exercises. Compared to the control condition, P300 amplitude decreased after high-intensity pedaling exercise and increased after medium-intensity pedaling exercise. There was no change after low-intensity pedaling exercise. These results suggested that the amount of attentional resources devoted to a given task decreased after high-intensity exercise and increased after medium-intensity exercise. The findings also suggest that changes in P300 amplitude are an inverted U-shaped behavior of differences in exercise intensity. In addition, no-go P300 amplitude showed the same changes as P300 amplitude at different exercise intensities. This indicates that differences in exercise intensity influenced not only the intensity of processing the requirement for a go response, but also processing of the need for a no-go response. It is concluded that differences in exercise intensity influenced information processing in the CNS.     

Kinetic analysis of thyrotropin-releasing hormone binding in the central nervous system: evidence for receptor desensitization

To investigate the mechanism(s) of experimentally and clinically observed refractoriness of spinal lower motor neurons (LMNs) to the excitatory effects of high-dose TRH, we examined the kinetics of dissociation of [3H]TRH from its CNS-receptor. At 23 degrees C, the receptor was rapidly (40 min) and completely converted from a form with fast dissociation kinetics (complex I; t1/2 20-30 min) to one from which the peptide dissociated much more slowly (complex II; t1/2 greater than 120 min). This conversion required the presence of added agonist ([3H]TRH) and was not prevented by the GTP-analog Gpp(NH)p. We suggest that complexes I and II may respectively represent active and inactive (desensitized) forms of the TRH-receptor and that TRH-induced I to II conversion of the receptor is responsible for refractoriness of LMNs to the drug.     

Electrophysiological evidence for adenosine receptors on astrocytes of cultured rat central nervous system

The actions of adenosine, R-N6-phenylisopropyladenosine (R-PIA) and N-(ethyl)carboxamidoadenosine (NECA) were tested on the membrane potential of astrocytes of cultured rat spinal cord and cerebellum. All 3 compounds hyperpolarized the majority of astrocytes studied. A considerable number of cells did, however, not respond to adenosine and its analogues, suggesting that only a certain type of astrocyte possesses adenosine receptors. The hyperpolarizations by adenosine, R-PIA and NECA were reversibly blocked by their antagonist 8-phenyltheophylline indicating that these compounds activate specific adenosine receptors. In agreement with biochemical and autoradiographic binding studies, our electrophysiological data strongly suggest the existence of adenosine receptors on astrocytes.     

Selective central nervous system tropism of primary central nervous system lymphoma

Primary Central nervous system lymphoma (PCNSL) is most frequently a diffuse large B cell lymphoma (DLBCL), which is confined to the Central nervous system (CNS). We performed an experiment in which lymphoma cells from a PCNSL patient were implanted subcutaneously in an athymic mouse. The lymphoma cells were shown to home to the CNS with histologic evaluations of the brain showing multiple large B cells in blood vessels consistent with intravascular large B cell lymphoma (IVL). We did not find any evidence of lymphoma at the site of implantation or other locations. The findings are consistent with highly selective tropism of PCNSLforthe CNS and its vasculature.     

Persistent central nervous system effects of an adverse early environment: clinical and preclinical studies

In the search for the underlying biological causes of psychiatric disorders, primary roles for both genetics and environment have been clearly established. A family history of mood or anxiety disorders, representing the genetic component, clearly increases the risk for developing these illnesses in adulthood. The pivotal role of early environmental influences in the pathogenesis of these disorders is also supported by an abundance of both clinical and preclinical data. This review will highlight some of the preclinical and clinical literature that suggests early adverse experience may sensitize corticotropin-releasing factor (CRF) circuitry. The neurobiology of depression highlighting the pathophysiological role of CRF is reviewed. Next, some of the preclinical models of early life stress are discussed; along with a review of the relevant clinical literature that suggests that the functional dysregulation of CRF circuitry in response to early life trauma may contribute to adulthood depression. The discussion will be framed in regards to a stress-diathesis model in which early adverse events result in a sensitized stress axis that predisposes individuals to develop mood disorders.     

Embryonic vertebrate central nervous system: Revised terminology

The layers and cells of the early developing central nervous system lack direct counterparts in the adult and must be designated by a special terminology. The inconsistent and inaccurate language now in use leads to misunderstanding and a revision is proposed in which the four fundamental zones are termed the ventricular, subventricular, intermediate, and marginal zones. Each is defined according to the form, behavior, and fate of its constituent cells. All neurons and macroglia of the central nervous system can be derived from these developmental zones.     

Spike timing, synchronization and information processing on the sensory side of the central nervous system

To what extent is the variability of the neuronal responses compatible with the use of spike timing for sensory information processing by the central nervous system? In reviewing the state of the art of this question, I first analyze the characteristics of this variability with its three elements: synaptic noise, impact of ongoing activity and possible fluctuations in evoked responses. I then review the recent literature on the various sensory modalities: somato-sensory, olfactory, gustatory and visual and auditory processing. I emphasize that the conditions in which precise timing, at the millisecond level, is usually obtained, are conditions that usually require dynamic stimulation or sharp changes in the stimuli. By contrast, situations in which stimulation not belonging to the temporal domain is temporally encoded lead to much coarser temporal coding; although in both cases, neural networks transmit the signals with similarly high precision. Synchronization among neurons is an important tool in information processing in both cases but again seems to act either at millisecond or tens of millisecond levels. Information theory applied to both situations confirms that the average rate of information transmission is much higher in dynamic than in static situations. These facts suggest that channels of precise temporal encoding may exist in the brain but imply populations of neurons working in a yet to be discovered way.     

Experimental and clinical application of plasmid DNA in the field of central nervous diseases

Novel therapeutic strategies utilizing plasmid DNA (pDNA) have been sought for non-treatable neurological disorders, such as ischemic stroke, Parkinson disease (PD), Alzheimer disease (AD), and multiple sclerosis (MS). One strategy is to induce overexpression of growth factors, such as vascular endothelial growth factor (VEGF), glial cell-line derived neurotrophic factor (GDNF), and hepatocyte growth factor (HGF), in the brain. Since ischemic stroke, PD, and AD show damage of neurons, the transfer of pDNA encoding these genes has been examined and shown to protect neurons from damage, associated with a better behavioral outcome. These growth factors have also been shown to accelerate angiogenesis, neurite outgrowth, and neurogenesis in the brain, and overexpression of these factors showed therapeutic effects in cerebral ischemia in rodents. Another application of pDNA is as a "DNA vaccine" to induce immunity against amyloid Aβ in AD, which requires a predominantly Th2 response to avoid autoimmune encephalomyelitis evoked by a Th1 response. Since the combination of pDNA and special devices and/or modification of pDNA could induce a predominantly Th2 response to a targeted antigen, a pDNA-based vaccine would be ideal for AD. Interestingly, pDNA could also induce immune tolerance, and pDNA-based vaccines to induce immune tolerance to autoimmune antibodies have been extensively examined in an animal model of MS. Based on the results, a pDNA vaccine has already been tried in MS patients and reported to be safe and partly effective in phase I/II clinical studies. In this review, we discuss the potential and problems of pDNA-mediated medicine in neurological disorders.     

Temporal characteristics of auditory sensory memory: Neuromagnetic evidence

We investigated the temporal dependencies of N100m, the most prominent deflection of the auditory evoked response, using whole-head neuromagnetic recordings. Stimuli were presented singly or in pairs (tones in the pair were separated by 210 ms) at interstimulus intervals (ISIs) of 0.6–8.1 s. N100m to single stimuli and to the first tone of the pair had similar temporal recovery functions, plateauing at ISIs of 6 s. N100m to the second tone in the pair, which was smaller than that to the first except with short ISIs, plateaued with ISIs of about 4 s. Source analysis revealed that the N100m could be decomposed into two sources separated by about 1 cm on the supratemporal plane. The recovery function of the posterior source was not affected by stimulus presentation, whereas that of the anterior source was. Activity in the anterior area appears to reflect the effects of temporal integration. We relate these results to auditory sensory memory.     

Primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is an uncommon extranodal non-Hodgkin lymphoma. Its incidence has increased during the last 3 decades and has been reported in both immunocompromised and immunocompetent patients. Immunocompromised patients are affected at a younger age compared with immunocompetent patients. It presents with raised intracranial pressure and focal neurologic and neuropsychiatric symptoms. The lesions are typically solitary. The majority of the lesions are located in the periventricular area, whereas in a few cases they are located in the supratentorial area. Diffuse large B-cell lymphomas constitute most PCNSLs, whereas T-cell, low-grade, anaplastic, and Hodgkin lymphomas are rarely encountered. The morphology of PCNSL shows a characteristic angiocentric pattern and is positive for B-cell markers by immunohistochemistry. The differential diagnosis of PCNSL includes central nervous system gliomas, metastatic tumors, demyelinating disorders, subacute infarcts, and space-occupying lesions due to an infectious etiology. The understanding of the molecular mechanisms involved in the pathogenesis of PCNSL and the identification of molecular biomarkers have lagged behind that of systemic nodal lymphomas. Primary central nervous system lymphomas are treated with combined radiotherapies and chemotherapies. The prognosis for PCNSL is worse than for other extranodal lymphomas.     

Mammalian central nervous system axolemma: histochemical evidence for axonal plasma membrane origin of bovine and rat axolemma-enriched membrane fractions

Purified myelinated axons were isolated from fresh bovine corpus callosum and rat brainstem and osmotically shocked to strip myelin and axolemma from axon filaments. Two axolemma-enriched fractions, myelin, and a pellet of myelin-free axons were harvested by discontinuous sucrose centrifugation of the shocked myelinated axons. By electron microscopy the axolemma-enriched fraction was composed of trilaminar membrane vesicles (diameter 50–1000 nm) and linear membrane fragments; myelin fragments were seldom seen but some mitochondria) membrane contamination was evident.The classical myelin stain Luxol Fast Blue never counter-stained the myelin-free axons, but did stain myelin, myelinated axons, and to a lesser extent, both axolemmal fractions. The staining of the axolemma-enriched fraction was amorphous and seemed incommensurate with the level of myelin contamination.Acetylcholinesterase staining of the axolemma-enriched fraction counterstained with Luxol Fast Blue revealed a number of acetylcholinesterase-positive membrane vesicles by light microscopy. Occasional enzyme-positive vesicles were also evident in the myelin while myelin-free axons showed virtually no Luxol Fast Blue stain but were heavily stained for the enzyme. Higher resolution histochemical staining by electron microscopy confirmed the light microscopy, showing acetylcholinest erase reaction product lining the axolemma of bovine and rat CNS neurons. Myelin, mitochondria, and other diverse membranes showed no reaction product. About 30% of bovine corpus callosal axons showed some acetylcholinesterase staining but only 3% of the total lengths of all the bovine CNS axolemma showed reaction product. Positive acetylcholinesterase staining could also be demonstrated in a small proportion of the bovine axolemma-enriched membranes, with reaction product lining the membrane fragments and captured within their vesicles. The percentage of vesicles that were stained closely agreed with the percentage of axolemma) length stained in the whole white matter.Since acetylcholinesterase staining was highly localized to the axonal plasma membrane, the acetylcholinesterase-positive membrane fragments in the axolemma-enriched membranes could only originate from the axolemma. We conclude on the basis of the operational behavior of these axolemmal vesicles that many of the membranes found in these fractions are derived from the axonal plasma membrane.