Changes In CNS Research Articles

Prevalence of stroke in Restless Legs Syndrome: Initial Results Point to the Need for More Sophisticated Studies

Background:Recent studies suggest a potential relationship between Restless Legs Syndrome (RLS) and hypertension and heart disease. Acute clinical stroke has been linked to the immediate onset of RLS, and epidemiological studies suggest the possibility that RLS may also lead to stroke.Methods:MRI scans from 26 RLS cases and 241 controls from the population based MEMO-Study (Memory and Morbidity in Augsburg Elderly) were assessed for the presence of clinical stroke, silent infarction, subcortical lesions and cortical atrophy. T1, T2, proton density images were obtained and infarcts and their characteristics were determined by visual inspection. RLS status was assessed according to the minimal criteria of the International RLS Study Group. Scans from the 26 RLS patients and a subset of 26 age and sex matched controls were reexamined by a separate rater using the same methodology. Descriptive statistics, logistic and linear regression models were used to determine the risk of the three types of CNS changes associated with RLS case status.Results:Among the 267 participants there was no difference in the prevalence of cardiovascular diseases or risk factors between RLS patients and the 241 controls. The prevalences of cerebrovascular events of all types, were greater in RLS patients, as were the amounts of cortical atrophy and the volume of subcortical lesions. However, these differences were not statistically significant. When age, sex and co-morbidities were taken into account in a logistic regression model, there was a statistically non-significant greater risk for stroke (Odds Ratio 2.46 with 95% CI 0.97-6.28, p = .06) associated with RLS case status. Conclusions:Future similar studies need to be performed on younger patients without other potential vascular risk factors, using Flair images and computerized programs for detection of cerebral ischemia. Improved methods for detection may allow for a reasonable sample size.

Pre and Post Natal Exposure of Fluoride Induced Oxidative Macromolecular Alterations in Developing Central Nervous System of Rat and Amelioration by Antioxidants

The effect of fluoride exposure during gestation and post gestation periods were studied to check the status of oxidant, antioxidant and macromolecular changes in CNS and ameliorative role of antioxidants. The pregnant Wistar albino rats were exposed to 50 and 150 ppm fluoride in drinking water and the pups born to them were used for experimentation. After postpartum, the pups were administered daily selected antioxidants through oral gavage. On 21st postnatal day pups were sacrificed and biochemical parameters were assessed. Fluoride exposure substantially increased the activity/levels of fluoride, LPO, protein oxidation, MAO-B, GOT, GPT and decreased protein thiols, RNA and total proteins in discrete regions of CNS. The findings evidenced fluoride induced dyshomeostasis caused on antioxidants, enzymes, macromolecules and governed the pathophysiological events leading to functional loss in a dose dependent manner. The administration of antioxidants remedied the disquiet caused by high fluoride exposure at extreme vulnerable periods of life.

De Novo Recruitment of Antigen-Experienced and Naive T Cells Contributes to the Long-Term Maintenance of Antiviral T Cell Populations in the Persistently Infected Central Nervous System

Mice infected with attenuated strains of mouse hepatitis virus, strain JHM, develop a chronic infection in the brain and spinal cord characterized by low levels of viral Ag persistence and retention of virus-specific CD4 and CD8 T cells at the site of infection. It is not known whether these cells are maintained by proliferation of T cells that entered the CNS during acute infection or are newly recruited from Ag-experienced or naive T cell pools. In this study, using adoptive transfer experiments and bone marrow chimeras, we show that at least some of these cells are recruited from the periphery, predominantly from the viral Ag-experienced T cell pool. Both virus-specific CD4 and CD8 T cells are functional, as assessed by cytokine expression and degranulation after peptide exposure. In addition, populations of virus-specific CD4 T cells undergo dynamic changes in the infected CNS, as previously shown for CD8 T cells, because ratios of cells responding to two CD4 T cell epitopes change by a factor of five during the course of persistence. Collectively, these results show that maintenance of T cell responses in the virus-infected CNS is a dynamic process. Further, virus-specific T cell numbers at this site of infection are maintained by recruitment from peripheral Ag-experienced and naive T cell pools.

Influence of Vagotomy on Monosynaptic Transmission at Second-Order Nucleus Tractus Solitarius Synapses

Manipulations of vagal activity are used to treat medical pathologies, but the underlying CNS changes caused by these treatments are not well understood. Furthermore, heart and lung transplant as well as treatments for many gastrointestinal disorders result in section of the vagus nerve (vagotomy). Following unilateral vagotomy under isoflurane anesthesia of Sprague-Dawley rats, electrophysiological properties were recorded with whole cell patch techniques in horizontal brain stem slices. Vagotomy significantly reduced the median amplitude of evoked excitatory postsynaptic currents (evEPSCs; -121; n = 43) in the nucleus tractus solitarius (NTS) when compared with controls (-157 pA; n = 66; P < 0.05) but had no significant effect on the passive properties or on the average amplitude or frequency of miniature EPSCs. The degree of synaptic failure exhibited during a 50-Hz train of stimuli was used to define two separate classes of synapses: "low failure" and "high failure" (HF); failure rates <5 and > or =5%, respectively. HF synapses had significantly smaller median evEPSCs (-88 vs. -184 pA; P < 0.05). After vagotomy, the percentage of HF synapses nearly doubled to 56% (n = 24/43) when compared with controls (30%; n = 20/66). Additionally, the overall percentage of failures after the second to fifth stimuli significantly increased by at least twofold. These results suggest that vagotomy causes a decrease in synaptic efficacy by both increasing the overall percentage of synaptic failures and shifting the population of NTS synapses toward more HF transmission. In addition, the alterations due to vagotomy are likely to be presynaptic in nature.

Importance of complete abstinence from alcohol during pregnancy: enough evidence for justification?

The association between daily and binge alcohol-drinking episodes during pregnancy and the range of malformations and deficits seen in fetal alcohol spectrum disorder is well described in the literature. However, there is little evidence for low-dose prenatal ethanol exposure and child deficit. This article uses a structured approach to consider the evidence for an association between low-dose prenatal alcohol exposure and neurodevelopmental deficits in children. There is consistent evidence in numerous animal experiments for lasting CNS changes associated with low levels of exposure to alcohol. In epidemiological studies, there is evidence of differences in behavior in children exposed to low doses of alcohol. The results of animal and human studies support current recommendations for complete abstinence from alcohol after conception.

Vitamin A deficiency in chickens and CNS changes.

Vitamin A deficiency in chickens and CNS changes.

CNS changes after chronic sleep deprivation: roles in both food intake and metabolism

In humans and animal models, chronic sleep loss stimulates feeding and leads to metabolic interactions associated with signs of the metabolic syndrome and progression to diabetes II. Understanding how sleep deprivation might produce these effects is more complicated and involves dissection of central nervous system pathways that normally regulate food intake and those which control peripheral metabolism. For the former, hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) are key systems governing feeding. Sleep deprivation up‐regulates NPY and down‐regulates POMC in the hypothalamus that accounts for the hyperphagia. For the changes in metabolism, usually hyperphagia is accompanied by a slowing of metabolic rate but the opposite is seen in chronic sleep deprivation. The CNS's role in regulating metabolic rate is less well understood, although histamine may be involved. Central histamine neurons not only affect the maintenance of wakefulness, but are also regulators of peripheral metabolism via actions at the preganglionic sympathetic neurons. The rate‐limiting enzyme for histamine synthesis, histidine decarboxylase, is up‐regulated during sleep deprivation, and these changes predict the attenuation of body weight (prompted by hypermetabolism). The relationship of changes in histamine synthesis to those of glucose suggests that the amine might also be responsible for changes which lead to metabolic syndrome. Elevations in glucose:insulin ratios in sleep deprived rats were positively correlated with the extent of increased histidine decarboxylase gene expression. Together, these data raise the possibility that a dysregulation of histamine function when sleep is impaired might serve to trigger increased sympathetic tone and metabolic changes leading to diabetes.Supported by a Pilot and Feasibility grant from the Clinical Nutrition Research Unit of Maryland, P30DK072488.

WHIPLASH: CHRONIC ORGANIC BRAIN SYNDROME WITHOUT HYDROCEPHALUS EX VACUO

Eleven patients who had sustained whiplash injuries to the neck were studied by pneumo-encephalography, by a variety of psychological tests, and by psychiatric evaluation with a view to assessing whether organic CNS changes might, in some cases, be a consequence of such injuries. Patients with traumatic encephalopathy, and age- and sex-matched groups of patients served as control groups. Pneumoencephalography showed normal findings in the whiplash group as a whole, the width of the ventricular system being significantly smaller than that of patients with traumatic encephalopathy. Psychological tests and psychiatric evaluation indicated that organic brain pathology was present in the whiplash patients, although to a lesser extent than in patients with traumatic encephalopathy.

Resveratrol improves age-related changes in SAMP10 CNS

Resveratrol improves age-related changes in SAMP10 CNS

Central nervous system abnormalities in vaginismus

Objective To investigate possible altered CNS excitability in vaginismus. Methods In 10 patients with primary idiopathic lifelong vaginismus, 10 with vulvar vestibulitis syndrome accompanied by vaginismus and healthy controls we recorded EMG activity from the levator ani (LA) and external anal sphincter (EAS) muscles and tested bulbocavernosus reflex (BCR). Pudendal-nerve somatosensory evoked potentials (SEPs) were tested after a single stimulus. Pudendal-nerve SEP recovery functions were assessed using a paired conditioning-test paradigm at interstimulus intervals (ISIs) of 5, 20 and 40 ms. Results EMG in patients showed muscular hyperactivity at rest and reduced inhibition during straining. The BCR polysynaptic R2 had larger amplitude ( p < 0.01) and longer duration ( p < 0.01) in patients from both groups than in controls. In controls, paired-pulse SEPs were suppressed at the 5 ms ISI for N35–P40 ( p < 0.05) and P40–N50 ms ( p < 0.001) and facilitated at the 20 ms ISI for N35–P40 ( p < 0.05) and P40–N50 ( p < 0.05). No significant differences were found in the paired-pulse N35–P40 in patients and controls but the cortical P40–N50 at 20 ISI was facilitated in patients ( p < 0.05). Conclusions EMG activity is enhanced and the cortical SEP recovery cycle and BCR are hyperexcitable in vaginismus. Significance The neurophysiological abnormalities in patients with vaginismus indicate concomitant CNS changes in this disorder.

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague–Dawley rats 2–6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L 3–4) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons ∼ 40% ( n = 18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by ∼ 60% ( n = 19; P < 0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore, in cuff-implanted rats WDR neurons ( n = 5) responded to mechanical cutaneous stimulation with an exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.

SSR149415, a non-peptide vasopressin V1b receptor antagonist, has long-lasting antidepressant effects in the olfactory bulbectomy-induced hyperactivity depression model

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1b (V1b) receptor and the development of depression has been suggested; therefore, a vasopressin V1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V1b receptor antagonist may have long-lasting antidepressant activity.

Different impact of nicotine on cortical excitability in smokers and nonsmokers

Chronic nicotine intake influences cortical excitability via functional and structural CNS changes, as known from animal experiments. Similar results have been demonstrated in humans (Lang et al. 2007). Smokers with 10 hours abstinence of nicotine showed a significant stronger inhibition in terms of short afferent inhibition (SAI) and diminished intracortical facilitation (ICF). Here we aimed to investigate if these differences of cortical excitability between smoking and not smoking individuals are caused and enhanced by nicotine consumption or if smoking individuals reduce enhanced inhibition by acute nicotine intake. Therefore different parameters of cortical excitability were recorded before and after nicotine consumption in smokers and nonsmokers.

Cortical Hypoexcitability in Chronic Smokers? A Transcranial Magnetic Stimulation Study

Studies in animal models and humans indicate that chronic nicotine intake influences neuronal excitability, resulting in functional and structural CNS changes. The aim of the present study was to explore human primary motor cortex (M1) excitability with transcranial magnetic stimulation (TMS) in chronic smokers. A total of 44 right-handed volunteers, aged 20-30 years, participated in the study. Chronic smokers were compared with age- and sex-matched healthy nonsmokers. We tested cortical excitability with single- and paired-pulse TMS to the left M1 and short-latency afferent inhibition (SAI) by combining median nerve stimulation and motor cortex TMS. Compared with nonsmoking controls, chronic smokers showed a significantly larger amount of SAI, which is thought to depend upon the activity of cholinergic inhibitory circuits produced by somatosensory inputs. Moreover, TMS-evoked inhibitory cortical silent periods were prolonged, whereas paired-pulse intracortical facilitation and motor-evoked potentials during moderate contraction were reduced. The results suggest that chronic nicotine intake may not only strengthen cholinergic inhibitory circuits, but could also be associated with enhanced inhibitory and reduced facilitatory mechanism of specific neuronal circuits in motor cortex. These changes may form a physiological basis for neurobiological and behavioral variations associated with chronic smoking.

Treatment of fibromyalgia and its symptoms

The main symptoms of fibromyalgia syndrome (FM) are pain, stiffness, subjective weakness and muscle fatigue. Pain in FM usually fluctuates, as well as being ‘deep’ and is always associated with local or generalized tenderness (hyperalgesia and allodynia). The pathogenesis of such peripheral and/or CNS changes in FM is unclear, but peripheral tissue changes, specifically in muscles, have been implicated. Indirect evidence from interventions that attenuate tonic peripheral impulse input in patients with FM suggest that overall FM pain is dependent on nociception. More importantly, FM-associated widespread mechanical hyperalgesia and allodynia can also be improved or abolished by removal of peripheral pain impulse input. In addition, FM patients show evidence of abnormal stress reactivity, including blunting of the hypothalamic–pituitary–adrenal axis and increased autonomic nervous system responsiveness. Thus, therapeutic interventions in FM should target not only pain reductions, but also improvements of peripheral/central sensitization and neuroendocrine/autonomic abnormalities. Despite the complexity of FM, there are pharmacologic and non-pharmacologic interventions that are available that have clinical benefit. Present evidence indicates efficacy of antidepressants, cardiovascular exercise and cognitive behavioral therapy. Based on this evidence, a stepwise program emphasizing education, medications, exercise and cognitive therapy can be recommended.

Proteomic Profiling of Plasma in Huntington's Disease Reveals Neuroinflammatory Activation and Biomarker Candidates

Huntington's disease (HD) causes widespread CNS changes and systemic abnormalities including endocrine and immune dysfunction. HD biomarkers are needed to power clinical trials of potential treatments. We used multiplatform proteomic profiling to reveal plasma changes with HD progression. Proteins of interest were evaluated using immunoblotting and ELISA in plasma from 2 populations, CSF and R6/2 mice. The identified proteins demonstrate neuroinflammation in HD and warrant further investigation as possible biomarkers.

Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys

AMG 102, a fully human monoclonal antibody that binds to hepatocyte growth factor (HGF), is a potential cancer therapeutic agent because of its ability to disrupt HGF/c-Met signaling pathways which have been implicated in most tumor types. To support a phase 1 study, the pharmacokinetic and safety profile of AMG 102 was assessed in cynomolgus monkeys. Serum concentration-time data from single- (i.v. and s.c.) and repeated-dose (i.v.) studies of up to 13 weeks were used for pharmacokinetic analysis. Safety was assessed in a single-dose safety pharmacology study with i.v. doses of 0 (vehicle), 25, 100, or 300 mg/kg and a 4-week toxicity study with once weekly i.v. doses of 0 (vehicle), 5, 25, or 100 mg/kg. AMG 102 exhibited linear pharmacokinetics over a 600-fold dose range (0.5 to 300 mg/kg) with a mean terminal half-life of 5.6 days after i.v. dosing. Clearance and volume of distribution at steady state were 1.22 ml/h and 198.3 ml, respectively. Estimated bioavailability was 72% for s.c. administration. Antibody response to AMG 102 was observed in a small percentage of monkeys. No treatment-related cardiovascular, respiratory, or CNS changes were observed. Administration of AMG 102 for 4 weeks was well tolerated at doses up to 100 mg/kg. Potential treatment-related effects were limited to minimal/moderate gastric mucosa hemorrhage in the mid- and high-dose groups. The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.

Efficacy and safety of Voriconazole in immunocompromised patients – single centre experience

Summary Background Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children. Aim The objective of this study was to determine the safety and tolerability of the oral and i.v. formulations of voriconazole Vfend®, previously not reported in Poland. Materials/Methods Twenty consecutive children and young adults aged 1 to 25 years, submitted for blood and marrow transplantation (BMT), were recruited during 10 months. When suspected or verified breakthrough systemic fungal infection occurred while kept on primary prophylactic fluconazole regimen, all patients received two loading doses of i.v. or oral voriconazole 6–9 mg/kg every 12 hrs, followed by a maintenance dose of 3 mg/kg every 12 hrs for five doses. If well tolerated, the voriconazole dosage was increased to 4 mg/kg every 12 hrs thereafter. Results Fungal infection was possible in 15/20, organ involvement with pulmonary process in 13 pts; CNS changes in 2 pts. Fungal aetiology was proven in 3 children (pulmonary Aspergillosis in 2 and Candida krusei in 1 patient), and considered as probable in 2 patients, having lung (2) and CNS (1) involvement. Four patients died. Clinical and radiological improvement was obtained in 14 patients, while uncontrolled, progressive disease occurred in 1 patient. Transient visual disturbances occurred in one patient. Major caution is warranted due to drug interaction via the cytochrome P-450 system which may lead to unexpected toxicity of the coadministered drugs (e.g. Vinca alkaloids, cyclosporine, rifampicin, erythromycin, etc). Conclusions Voriconazole is an advantageous new azole well tolerated in 20 patients. Outcome in BMT breakthrough infections was good.

Life-span influences of apoE4 on CNS function

A major question in neurogerontology is what determines elective vulnerability of neurons during “normal” aging, nd how does aging modulate vulnerability in neural disrders induced by challenges from environmental (toxins nd trauma), and genetic (biochemical homeostasis) factors. Normal” aging must be distinguished from the slowly proressing, early effects of incipient Alzheimer’s disease (AD). n AD, vulnerability has been related to plasticity (which is trictly defined as the capacity to change) [5,79]. But what about aging? It is important to define the major tages of CNS changes in life. Human brain development nds approximately after the second decade of life, and since his represents one major turning point [8,62], this can be efined as the start of many aging processes. Every neuon “population” has an inherent vulnerability to “degenerte” in response to aging and/or to challenge. Vulnerability an be manifested as a neuron’s place in regional, connecional (network), biochemical, and temporal schemes. During evelopment, degenerative vulnerability in neuron “pruning” s largely activity-dependent. In AD, vulnerability follows a haracteristic biochemical, regional and connectional process i.e. entorhinal cortex, hippocampus, etc), which is driven priarily by age (as the only universal risk factor), but clearly odified by environmental and genetic factors. Mechanisic commonalities between developmental pruning and AD tiology have been described [8,50]. The major questions are what are the mechanisms at work n aging and, equally important, when do they start, and with hat do they interact. These are the issues raised by the results

Opiate Treatment for Patients in Chronic Non-Cancer Pain

Back to table of contents Previous article Next article Letters to the EditorFull AccessOpiate Treatment for Patients in Chronic Non-Cancer PainRonald Abramson M.D.,Ronald Abramson M.D.Search for more papers by this author,Published Online:1 Jul 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: I disagree with the global condemnation of the use of chronic high-dosage opiates for treating pain patients expressed by Jon Streltzer, M.D., and Luther Johansen, M.D., in the April 2006 issue of the Journal(1) . In their clinical case conference about an addicted woman with a pain syndrome, Drs. Streltzer and Johansen argue that there is too much careless prescribing of opiates by well meaning physicians. They maintain that such careless prescribing is fostered by a cultural belief system in the efficacy of opiates for treating chronic pain, a belief that is unsupported by solid evidence. I feel that this is an oversimplification of a complicated and tragic problem. In my view, there are two broadly defined populations of patients who come to our attention. One group includes patients with pain and addictive drug-seeking behavior, characterized by the woman discussed by Drs. Streltzer and Johansen, and the other group includes patients who have true nonpsychogenic chronic pain, without an addictive drug-seeking pattern of behavior. The treatment model cited by Drs. Streltzer and Johansen is undoubtedly efficacious for some pain drug-seeking patients but would be ineffective for nondrug-seeking, noncancer patients in true chronic pain. Opiates, of course, do cause CNS changes that may enhance pain sensitivity, but in spite of a paucity of controlled studies, they are generally endorsed by specialists as appropriate treatment for refractory pain (2) . Undoubtedly, treatment of chronic noncancer pain with opiates is a problem that requires a rigorous clinical approach, with careful screening for drug-seeking behavior and consideration of alternatives (3) . One key element in differentiating between the two patient populations mentioned above is to monitor the patient carefully enough to determine whether opiate treatment improves overall functioning or degrades it. Psychiatrists who frequently see patients for psychotherapy may be in a good position to make a reasonable, albeit fallible, determination about into which population their patients fall. Contrary to the position taken by Drs. Streltzer and Johansen—that there is a culture of over-prescribing opiates—it is my position that opiates are underprescribed by physicians out of a fear of legal retribution. It would be unfortunate if the opinions expressed by Drs. Streltzer and Johansen encourage psychiatrists to avoid attempting to treat this group of patients who sometimes have no alternatives to opiate treatment.Wayland, Md.