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Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure.

OBJECTIVES: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. BACKGROUND: Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. METHODS: Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. RESULTS: Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. CONCLUSIONS: Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.

Brain↗

Ultrastructural study of calycine synaptic endings of colossal vestibular fibers in the cristae ampullares of the developing chick.

Bipolar vestibular ganglion cells give rise to the colossal vestibular fibers in the chicken. These fibers form the largest calycine endings in the cristae ampullares and also the spoon endings in the tangential vestibular nucleus of the medulla oblongata. Because these synaptic endings are two of the largest and most distinctive in the vertebrate nervous system, they are especially suitable for comparisons of the development of synapses and synaptic endings of a specific cell type. An ultrastructural study of the spoon endings and quantitative data on their synapses were available from material of 15-day-old chick embryos, hatchlings, and 3-yr-old chickens. Here we provide similar data on the large calyces. Briefly, large calyces exhibited no ultrastructural changes corresponding to the changes in the spoon endings apparent when they retract from their target cell surfaces around hatching time. However, the concentration of the ribbon synapses at the large calyces decreased around hatching, when the concentration of the chemical synapses at the spoon endings declined. Moreover, the concentration of the ribbon synapses at the large calyces corresponded closely to the concentration of the chemical synapses at the spoon endings at the same age. Thus at the developmental ages studied, there were similar concentrations in the peripheral and central synapses formed at two different synaptic endings, both derived from one cell type and participating in the same neural pathway. These findings raise the issue of how synapses are regulated locally, but also suggest the possibility for central-peripheral interactions to produce correlative changes in parallel.

Animals↗

Cholinergic role in alcohol's effects on evoked potentials in visual cortex of the albino rat.

Photic evoked potentials were recorded from the visual cortex of chronically implanted albino rats. Since photic evoked potential components are representations of neural pathways which are activated during photic stimulation, study of the effects of alcohol on these components may help to trace pathways which are affected by alcohol. In the present study, evoked potentials were recorded at 5, 20, and 40 min following IP injections of saline, ethanol (2.0 g/kg), physostigmine (0.6 mg/kg) or atropine (15.0 mg/kg) on separate days. Ethanol depressed the amplitudes of most evoked potential components in comparison to saline administration. Component P2, however, was increased in amplitude. Physostigmine briefly reduced the amplitude of most components, including P2. In contrast, atropine increased the amplitudes of components P1 and P2, while decreasing components N1, N2 and N3 for varying durations of time. Physostigmine pretreatment augmented the depressant effect of alcohol on the early components P1 and N1, while attenuating alcohol's influence on components P2 and P3. Pretreatment with atropine likewise further reduced the amplitudes of components P1 and N1, and produced a similar effect on component N3. Atropine, either alone or in combination with alcohol, produced approximately the same degree of enhancement of component P2. In comparison to saline values, all three agents produced reliable increases in peak latency for most of the components, with only N3 showing no effects. The amplitude data from this study suggest that ethanol's augmentation of component P2 may result, at least in part, from alterations in cholinergic functions.

Animals↗

Changes in neuromuscular reflexes in the masseter muscles during functional jaw orthopedic treatment in children.

Masseteric reflexes following standardized taps on an upper incisor were recorded electromyographically (1) in children with Class II, Division 1 malocclusions at different times before and during the treatment with the Bionator functional appliance and (2) during an observation period in control subjects who were not being treated. In each experimental session, 72 taps were delivered during clenching at 10% of the maximal electromyographic output. Statistical criteria provided by a previously developed computer program allowed the objective determination of inhibitory and excitatory periods in the electromyographic output following the stimulus, which together constitute the poststimulus electromyographic complex (PSEC). The influence of the change in occlusal relations on the PSEC was determined in ten subjects by comparing pretreatment results with those obtained after 1, 3, and 6 months of treatment. Concurrent with an improvement of the sagittal jaw relation in the patients with a pronounced disharmony, a short latency excitatory peak appeared in their PSECs. It was demonstrated by averaging nonrectified electromyographic activity that this peak was brought about through synchronization of motor units. In the control group, however, the morphology of the PSEC was reproducible over time. Successful functional therapy is thus accompanied by specific transient changes in the reflex response of the masseter muscles to standardized tooth taps. The neural pathways contributing to these observations originate in periodontal and muscular receptors, and might provide a clue for the mechanism underlying successful functional treatment.

Activator Appliances↗

Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress.

We have demonstrated previously that chronic administration of morphine, cocaine, or ethanol produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing and locomotor activating properties of these drugs of abuse. Because this neural pathway is also regulated by stress, and because stress has been shown to influence an animal's behavioral responses to drugs of abuse, it was of interest to determine whether repeated exposure to stress results in similar biochemical adaptations. By use of immunoblot analysis, we show here that a course of chronic "unpredictable" stress, like chronic drug exposure, increased levels of immunoreactivity of tyrosine hydroxylase and glial fibrillary acidic protein and decreased levels of immunoreactivity of neurofilament proteins in the VTA. Chronic unpredictable stress also increased levels of cyclic AMP-dependent protein kinase activity and decreased levels of immunoreactivity of the G protein subunit, Gi alpha, in the NAc. These effects required long-term exposure to stress and were in most cases not seen in the substantia nigra and caudate-putamen, components of the nigrostriatal dopamine system studied for comparison. The biochemical effects of chronic stress in the VTA and NAc differed among three strains of rat studied. Fischer 344 rats were the most responsive in that they exhibited all of the aforementioned adaptations, whereas Lewis rats were the least responsive in that they exhibited none of these adaptations; Sprague-Dawley rats exhibited an intermediate number of responses. Taken together, the results of the present study demonstrate that chronic exposure to stress results in biochemical adaptations in the mesolimbic dopamine system that resemble the chronic actions of several drugs of abuse. These adaptations could contribute to the convergent behavioral effects induced by treatments that are mediated via the VTA-NAc pathway.

Adaptation, Physiological↗

Development of muscle nerve in the teleost fish, medaka.

The entire process of normal development of a muscle nerve to a muscle (middle interradial muscle) in the tail region of the medaka (Oryzias latipes) is briefly reported. The nerve was stained immunohistochemically by using anti-neurofilament protein antibodies or stained by HRP and DiI labeling methods. The muscle was stained immunohistochemically by using anti-troponin T and anti-desmin antibodies. The smallness and transparency of the medaka embryos provide us with an opportunity to examine nerve-muscle development in whole-mount specimens. Our observations suggest that prior to the appearance of the middle interradial muscle a neural pathway has established, extending from the starting point to the 'door step' of the muscle.

Animals↗

Nicergoline in the treatment of dizziness in elderly patients. A review.

In elderly patients, dizziness occurs very frequently with significant effects on the patient's life. Its frequency increases with age, and may arise from a variety of causes. Chronic dysequilibrium in elderly patients is most probably related to disturbances within the central nervous system, due either to altered neuronal functions or to an underlying vascular disease. Nicergoline, a drug used in the treatment of cognitive disturbances in geriatric patients, improves dizziness in elderly demented and non-demented patients. In a double blind,placebo controlled trial the drug improved (i) the severity of symptoms, measured by the dizziness assessment rating scale (DARS), (ii) the overall clinical conditions revealed by global impression scale, and (iii) the perceived quality of life estimated by the dizziness handicap inventory (DHI). These results indicate a possible positive effect also on posturographic measures. Moreover, the improvement occurred at no expense of the established strategy of postural control suggesting that the effect is mediated by a substitute compensatory mechanism allowing the patient to preserve consolidated postural strategies. The results of previous open clinical studies in about 3000 patients are in agreement with those findings. Overall, severity of symptoms decreased by 68 % (57 % in the control study). Globally, the results indicate a beneficial effect of nicergoline on symptoms related to balance disorders of central origin. Animal studies show that the drug displays a broad spectrum of actions on cellular and molecular mechanisms. Moreover, animal research specifically aimed at vestibular pathophysiology has revealed that nicergoline improves vestibular compensation in models of vestibular lesion. Chronic treatment with nicergoline improved the time-course of behavioral recovery in old rats after hemi-labyrinthectomy and counteracted the regulation of cholinergic receptors observed after lesion in old rats. Nicergoline interacts at several levels by various mechanisms, from the molecular level to cognitive function, probably enhancing spontaneous plasticity phenomena underlying the central vestibular compensation. This effect is not dependent from the interaction with a single-transmitter-identified neural pathway, but from anatomical, functional and neurochemical synergistic adjustments in several brain areas.

Aged↗

Unilateral or bilateral vagotomy performed on prepubertal rats at puberty onset of female rat deregulates ovarian function.

BACKGROUND: Injecting a neurotoxin virus into ovary of adult rats has provided morphologic evidence of a multisynaptic neural pathway between ovary and central nervous system (CNS). Vagus nerve is one of the pathways used by CNS to send and receive information to and from the ovary. METHODS: The present study analyzed whether or not vagal innervation of ovaries in prepubertal rats modulated, in a stimulatory fashion, functions of the ovary and whether the modulating function of these nerves was asymmetric. RESULTS: Animals vagotomized at 24 and 28 days of age showed delay in age of onset of puberty. Unilateral or bilateral vagotomy performed at 24 days of age did not modify ovulation rates or number of ova shed. In turn, bilateral vagotomy performed at 28 days of age resulted in a significant increase in number of ova shed by ovulating animals. Unilateral and bilateral vagotomy performed on day 24 or 28 resulted in a decrease in estradiol serum levels. Unilateral vagotomy performed on 24-day-old rats did not modify progesterone levels, while bilateral vagotomy on the same age group resulted in a significant increase of progesterone levels. In turn, unilateral and bilateral vagotomy performed on rats aged 28 days resulted in lower progesterone levels. CONCLUSIONS: Present results confirmed results of previous studies, indicating that interrupting ovarian innervation had an effect on regulation of ovarian functions by CNS and that these effects varied according to age at which denervation was performed.

Age Factors↗

The emerging fragile X premutation phenotype: evidence from the domain of social cognition.

Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200) region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP). Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation ("carrier-status") (approximately 55-200 repeats). Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The findings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.

Adolescent↗

Stereoscopic depth magnitude estimation: effects of stimulus spatial frequency and eccentricity.

To determine the effects of stimulus spatial frequency and retinal eccentricity on the perception of depth magnitude derived from disparity cues alone, subjects were asked to estimate the magnitude of depth of a stereoscopically viewed Gabor patch presented to the central or peripheral field with either crossed or uncrossed absolute disparity. Disparity vergence responses to the same Gabor stimuli were separately estimated subjectively by determining the offset required for dichoptic nonius alignment following presentation of the stimulus. The normalized stereoscopic magnitude estimation data generally showed that crossed disparities were perceived with greater depth than uncrossed disparities of the same magnitude, whether presented to the central or peripheral field. Asymmetries in magnitude of depth perception ranged from mild differences between depth directions to complete lack of depth perception for one direction. Disparity vergence response functions varied from (1) appropriate initiation of vergence to both directions of disparity, (2) initiation of vergence to only one direction of disparity, or (3) an attenuated initiation of vergence response to either direction of disparity. Within subjects, their asymmetries in magnitude of depth perception did not correlate with their asymmetries in vergence initiation. The similarity of the asymmetric depth magnitude estimation for a given individual at both stimulus locations tested suggests that common neural mechanisms are responsible for central and peripheral depth magnitude estimation. The lack of correlation between the perceptual and motor responses to the same stimuli suggests that the neural pathways for these responses diverge shortly after the detection of disparity in primary visual cortex.

Adult↗

Unilateral electrical stimulation of the inferior colliculus of rats modifies the prepulse modulation of the startle response (PPI): effects of ketamine and diazepam.

The magnitude of an acoustic startle response can be reduced by a weak stimulus presented immediately before the startle-eliciting noise. This phenomenon has been termed prepulse inhibition of the startle reaction (PPI). Previous studies indicated that the primary neural pathways mediating PPI belong to the brain stem and that the inferior colliculus (IC) was crucial. Its destruction reduced PPI. Stimulations applied to brain areas may be as deleterious as lesions. Therefore, we looked for the possibility of a brain stimulation applied to the IC during a PPI test to reduce also PPI. Rats were implanted with chronic electrodes, their tips being aimed at the IC. They were located within or close to the inter-colliculus nucleus. A train of stimulations was applied and PPI was tested alternately during and between periods of stimulation. As the most common method used to attenuate PPI consists in administrating drugs, for example ketamine, we also tested the effect of this drug. Another drug was also tested, diazepam, since it alters the functioning of the IC without any known effect on PPI. This allowed a comparative analysis of the neurobiological and the pharmacological effects. It appeared that the stimulation decreased PPI quantitatively as much as ketamine (6 mg/kg) without an effect of the basic startle reaction. These effects did not interfere with each other. Diazepam (1 mg/kg) did not modify PPI, neither under stimulation nor per se. Only for a very high dose (4 mg/kg), a sedative and myo-relaxant one the basic startle and PPI were altered.

Acoustic Stimulation↗

Passage of murine scrapie prion protein across the mouse vascular blood-brain barrier.

Prions are the infectious agents associated with transmissible spongiform encephalopathies and are composed mainly of a misfolded form of the endogenous prion protein. Prion protein must enter the brain to produce disease. Previous work has emphasized various mechanisms which partially bypass the blood-brain barrier (BBB). Here, we used the brain perfusion method to directly assess the ability of mouse scrapie protein (PrP(SC)) to cross the mouse BBB independent of the influences of neural pathways or circulating immune cells. We found that PrP(SC) oligomers rapidly crossed the BBB without disrupting it with a unidirectional influx rate of about 4.4microl/g-min. HPLC and capillary depletion confirmed that PrP(SC) crossed the entire width of the capillary wall to enter brain parenchyma. PrP(SC) also entered the cerebrospinal fluid (CSF) compartment. These results show that a prion protein can cross the intact BBB to enter both the parenchymal and CSF compartments of the brain.

Animals↗

Neural correlates of executive function in autistic spectrum disorders.

BACKGROUND: Some clinical characteristics of high-functioning individuals with autistic spectrum disorder (ASD) such as repetitive stereotyped behaviors, perseveration, and obsessionality have been related to executive function (EF) deficits, more specifically to deficits in inhibitory control and set shifting and mediating frontostriatal neural pathways. However, to date, no functional imaging study on ASD has investigated inhibition and cognitive flexibility and no one has related EF brain activation to brain structure. METHODS: We compared brain activation (using functional magnetic resonance imaging) in 10 normal intelligence adults with ASD and 12 healthy control subjects during three different EF tasks: 1) motor-inhibition (GO/NO-GO); 2) cognitive interference-inhibition (spatial STROOP); and 3) set shifting (SWITCH). Using voxel-based morphometry, we investigated if cortical areas which were functionally different in people with ASD were also anatomically abnormal. RESULTS: Compared with control subjects, ASD individuals showed significantly increased brain activation in 1) left inferior and orbital frontal gyrus (motor-inhibition); 2) left insula (interference-inhibition); and 3) parietal lobes (set shifting). Moreover, in individuals with ASD, increased frontal gray matter density and increased functional activation shared the same anatomical location. CONCLUSIONS: Our findings suggest an association between successful completion of EF tasks and increased brain activation in people with ASD, which partially may be explained by differences in brain anatomy.

Adolescent↗

Fronto-hippocampal function during temporal context monitoring in schizophrenia.

BACKGROUND: Patients with schizophrenia have difficulty using contextual information to recall the source of information. Given the importance of the hippocampus and prefrontal cortex (PFC) in this type of memory, we hypothesized that this cognitive deficit stemmed from aberrant fronto-hippocampal activation during memory retrieval. METHODS: Patients with schizophrenia (n = 16) and age-matched comparison subjects (n = 16) underwent functional magnetic resonance imaging while performing a verbal memory task that requires intact use of temporal context. Blood oxygen-level dependent (BOLD) signal during correct memory decisions was compared between the two groups with statistical parametric mapping. RESULTS: Contrary to our hypotheses, patients with schizophrenia demonstrated nearly identical memory performance to that of the comparison subjects. Despite this, there were significant between-group BOLD signal differences, including a pattern of task-dependent hypofrontality or hyperfrontality. In addition, whereas the highest-performing subset of the comparison group demonstrated robust modulation of hippocampal activity, this pattern was not seen in the highest-performing patients with schizophrenia. CONCLUSIONS: Despite memory performance similar to that of comparison subjects, patients with schizophrenia activated different neural pathways to achieve this success. This might reflect underlying neuropathology in fronto-hippocampal circuitry, the use of an alternate cognitive strategy to accomplish task performance, or both.

Adult↗

Corticosterone release is heightened in food or water deprived oxytocin deficient male mice.

Recent studies in female mice that cannot synthesize oxytocin (OT) suggest that central OT neural pathways attenuate the response of the hypothalamic-pituitary-adrenal (HPA) axis to certain stressors. OT deficient (OT-/-) female mice had higher plasma corticosterone concentrations than wild type (OT+/+) female mice following exposure to platform shaker (Mantella et al., 2004). The present study examined the corticosterone response of OT-/- and OT+/+ male mice that were exposed to shaker stress or other stressors (i.e., administration of cholecystokinin (CCK), dehydration, or fasting) that are known to activate central OT neurons in mice. Plasma corticosterone concentrations were higher in male mice receiving each stress than in male mice not exposed to a stressor. Plasma corticosterone concentrations were higher in OT-/- than OT+/+ male mice that were water deprived (P < 0.05) or fasted (P < 0.03), whereas corticosterone concentrations following exposure to platform shaker or CCK administration (10 microg/kg i.p.) were not different between genotypes. These findings support the hypothesis that absence of OT results in a heightened response of the HPA axis to certain stressors and that OT can attenuate the corticosterone response associated with overnight food or water deprivation in male mice.

Animals↗

The neonatal tear film.

The importance of the tear film for the integrity of the ocular surface is well established. Full-term neonates produce tears normally, but low spontaneous blink rates during early life raises important questions regarding tear dynamics and stability. Although an afferent neural pathway that could potentially detect tear break-up is in place at birth, there is indirect evidence that the neonatal tear film is adapted to resist evaporation-mediated tear thinning. This adaptation presumably prevents drying of the ocular surface during long inter-blink periods. However, low rates of tear turnover may have important implications for the defence of the eye against potential pathogens.

Journal Article↗

Transcranial magnetic stimulation--a sandwich coil design for a better sham.

OBJECTIVE: To improve the quality of TMS studies by developing a new sham condition. METHODS: We describe a novel and easily arranged TMS set-up of two standard TMS coils and a magnetic shield, stacked like a sandwich. In a first step we compare the magnetic field in the sham and verum conditions. In a second step we ask six subjects to rate the stimulation intensity. RESULTS: The magnetic field in the sham mode is reduced to about one eighth of that during verum stimulation. The attenuation of the magnetic field is not limited to the actual stimulation site but also effective at neighbouring brain areas, avoiding direct and indirect stimulation via connected neural pathways. This also minimizes stimulation of the skin, but as a consequence allows subjects to distinguish between verum and sham conditions when these are contrasted directly. The position of the coil system and the acoustic sensations are indistinguishable between sham and verum condition. Subjects are not able to discriminate TMS position and condition by external cues. CONCLUSIONS: The proposed TMS setup is simple and allows verum and sham TMS without interaction of the researcher. If used with the magnetic shield, the magnetic field in the brain is attenuated most. SIGNIFICANCE: With the sandwich TMS coil system it is possible to improve the quality of TMS studies.

Adult↗

Distinct cortical and collicular mechanisms of inhibition of return revealed with S cone stimuli.

Visual orienting of attention and gaze are widely considered to be mediated by shared neural pathways, with automatic phenomena such as inhibition of return (IOR)--the bias against returning to recently visited locations--being generated via the direct pathway from retina to superior colliculus (SC). Here, we show that IOR occurs without direct access to the SC, by using a technique that employs stimuli visible only to short-wave-sensitive (S) cones. We found that these stimuli, to which the SC is blind , were quite capable of eliciting IOR, measured by traditional manual responses. Critically, however, we found that S cone stimuli did not cause IOR when saccadic eye movement responses were required. This demonstrates that saccadic IOR is not the same as traditional IOR, providing support for two separate cortical and collicular mechanisms of IOR. These findings represent a clear dissociation between visual orienting of attention and gaze.

Adult↗