Institute of Higher Nervous Activity and Neurophysiology

Evidence-based practice is a systematic approach to problem solving for health care providers, including RNs, characterized by the use of the best evidence currently available for clinical decision making, in order to provide the most consistent and best possible care to patients. Are RNs in the United States prepared to engage in this process? This study examines nurses' perceptions of their access to tools with which to obtain evidence and whether they have the skills to do so. Using a stratified random sample of 3,000 RNs across the United States, 1,097 nurses (37%) responded to the 93-item questionnaire. Seven hundred sixty respondents (77% of those who were employed at the time of the survey) worked in clinical settings and are the focus of this article. Although these nurses acknowledge that they frequently need information for practice, they feel much more confident asking colleagues or peers and searching the Internet and World Wide Web than they do using bibliographic databases such as PubMed or CINAHL to find specific information. They don't understand or value research and have received little or no training in the use of tools that would help them find evidence on which to base their practice. Implications for nursing and nursing education are discussed.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

The modified Hopfield model defined in terms of " V -variables" ( V = 0; 1), which is appropriate for storage of correlated patterns, is considered. The learning algorithm is proposed to enhance significantly the storage capacity in comparison with previous estimates. At low levels of neural activity, p ≪ 1, we obtain α c ( p ) ∼ ( p |ln p |) -1 which resembles Gardner's estimate for the maximum storage capacity.

Repeated use of brain-computer interfaces (BCIs) providing contingent sensory feedback of brain activity were recently proposed as a rehabilitation approach to restore motor function after stroke or spinal cord lesions. However, there are only a few clinical studies that investigate feasibility and effectiveness of such an approach. Here we report on a placebo-controlled, multicenter clinical trial that investigated whether stroke survivors with severe upper limb (UL) paralysis benefit from 10 BCI training sessions each lasting up to 40 minutes. A total of 74 patients participated: median time since stroke is 8 months, 25% and 75% quartiles [3.0; 13.0]; median severity of UL paralysis is 4.5 points [0.0; 30.0] as measured by the Action Research Arm Test , ARAT, and 19.5 points [11.0; 40.0] as measured by the Fugl-Meyer Motor Assessment, FMMA. Patients in the BCI group (n=55) performed motor imagery of opening their affected hand. Motor imagery-related brain electric activity was translated into contingent hand exoskeleton-driven opening movements of the affected hand. In a control group (n=19), hand exoskeleton-driven opening movements of the affected hand were independent of brain electric activity. Evaluation of the UL clinical assessments indicated that both groups improved, but only the BCI group showed an improvement in the ARAT’s grasp score from 0 [0.0; 14.0] to 3.0 [0.0; 15.0] points (p<0.001) and pinch scores from 0.0 [0.0; 7.0] to 1.0 [0.0; 12.0] points (p<0.001). Upon training completion, 21.8% (36.4%) of the patients in the BCI group improved their ARAT (FMMA) scores. The corresponding numbers for the control group were 5.3% (ARAT) and 15.8% (FMMA). These results suggests that adding BCI control to exoskeleton-assisted physical therapy can improve post-stroke rehabilitation outcomes. Both maximum and mean values of the percentage of successfully decoded imagery-related EEG activity, were higher than chance level. A correlation between the classification accuracy and the improvement in the upper extremity function was found. An improvement of motor function was found for all patients independently of duration, severity and location of the stroke. Clinical trial registration number: NCT02325947.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3beta is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3beta phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3beta. The LTP deficits can be attenuated/rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3beta in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.

Existence of the theoretically predicted spiral waves of excitation in intact two-dimensional networks of excitable elements has been experimentally confirmed in the isolated chicken retina. The preparation supports the waves of Leão's spreading depression (SD) the concentric propagation of which from the point of origin can be directly observed as a change of the optical properties of the retinal tissue. The propagation rate of 3.7 mm/min (35 degrees C) decreased to 1.5 mm/min for SD waves elicited during relative refractory period. When a several-mm long segment of the SD wave had been blocked by anodal polarization, the laterally opened ends of the wavefront started to spread after termination of polarization into the previously blocked tissue, gradually turning around and penetrating into the region recovering from the original SD. One or two simultaneously generated spiral waves of SD continued to rotate for several cycles. Spiral SD could also be elicited by punctiform cathodal polarization (1 mA) applied to the SD wave-rear. Since the new SD wave could only spread into the recovering tissue it formed a laterally open wavefront, the free ends of which eventually turned around and started spiral SD. With continued reverberation the nucleus of the spiral SD wave gradually migrated across the retina until it approached an obstacle (e.g., pecten) which stopped further spiral propagation. Spiral SD waves were elicited in 31 retinal preparations and lasted for 4.5 cycles on the average. Average cycle duration was 4.7 min. Spontaneous spiral SD waves were observed in preparations incubated in Mg2+-free media. The spiral SD waves in retina are compared with mathematical models of analogous phenomena. It is argued that spiral SD waves probably exist in the cerebral cortex of rats and account for generation of repetitive SD waves sometimes elicited by overlapping stimulation of two cortical regions.

Slow-wave sleep is characterized by spontaneous alternations of activity and silence in corticothalamic networks, but the causes of transition from silence to activity remain unknown. We investigated local mechanisms underlying initiation of activity, using simultaneous multisite field potential, multiunit recordings, and intracellular recordings from 2 to 4 nearby neurons in naturally sleeping or anesthetized cats. We demonstrate that activity may start in any neuron or recording location, with tens of milliseconds delay in other cells and sites. Typically, however, activity originated at deep locations, then involved some superficial cells, but appeared later in the middle of the cortex. Neuronal firing was also found to begin, after the onset of active states, at depths that correspond to cortical layer V. These results support the hypothesis that switch from silence to activity is mediated by spontaneous synaptic events, whereby any neuron may become active first. Due to probabilistic nature of activity onset, the large pyramidal cells from deep cortical layers, which are equipped with the most numerous synaptic inputs and large projection fields, are best suited for switching the whole network into active state.

OBJECTIVES: To examine the mechanisms of alternative strategies developed by stroke patients to compensate their motor impairment and their role in recovery. MATERIAL AND METHODS: The three-dimensional kinematics of the upper limb were quantified during unconstrained reaching movements in seven healthy individuals and in 15 stroke patients. Nine patients were followed-up. Individual observations were correlated with anatomical and functional brain imaging described elsewhere (Feydy et al. Stroke 2002;33:1610). RESULTS: Healthy subjects used mainly elbow extension and shoulder flexion, scaled to movement distance. Patients with hemiparesis because of stroke used different patterns of joint recruitment with different scaling rules. Patients with the greatest impairment compensated by recruiting extra degrees of freedom, particularly trunk bending. Improvement was because of a restoration towards a normal movement pattern (recovery) and/or to a reinforcement of compensation, which led to a poorer outcome. CONCLUSION: Individual behavioural data are necessary to discuss the mechanisms of functional improvement following stroke with respect to recovery and/or compensation.

Golgi-impregnated and gold-toned preparations of cat hippocampus were studied under the light and electron microscope in order to characterize synapses in contact with the axon initial segments of pyramidal neurons. The initial segment of the axon emits spine-like appendages and it was sometimes seen to be in apparent contact with thin varicose fibers that climbed along it. The latter type of varicose axon terminal segments occurred at the base of pyramidal neurons in all regions of the hippocampus and in the subiculum: they are 20 to 40 w long, contain 3 to 15 varicose swellings, and are interconnected by thin horizontal or arcadic fibers. It was established by electron microscopy of gold-toned material that light microscopically identified varicosities of these terminal segments were in symmetrical synaptic contact exclusively with axon initial segments; four of the initial segments in the CA1 region could be traced back to pyramidal neurons. Thus the pyramidal cell of the cat hippocampus receives input along its axon initial segment from boutons that probably originate from axoaxonic cells of the type found previously in the cerebral cortex and monkey hippocampus.

Although calmodulin is generally regarded as a soluble protein, a considerable amount of calmodulin activity was found to be associated with particulate fractions of mammalian tissues after an extensive washing of the particulate fraction with EGTA. Identity of this particle-bound and EGTA-nonextractable form of calmodulin with soluble calmodulin was established recently (Sobue, K., Yamazaki, R., Yasuda, S., & Kakiuchi, S. (1981) FEBS Lett. 129, 215-219). The particle-associated calmodulin activity was latent to some extent and its unmasking required the presence of nonionic detergent. We have developed an assay method for the soluble and particulate forms of calmodulin in biological samples and, by means of this method, concentrations of calmodulin in rat and bovine tissues were quantitatively determined. In the supernatant, high levels (greater than 10 microM) of calmodulin were found in the testis, pituitary gland, and various areas of brain, intermediate levels (5-10 microM) in the liver, kidney, and spleen. Particulate fractions contained 10-50% of the total calmodulin contents in the tissues. Human erythrocytes contained (2.5 +/- 0.2) microM calmodulin, or (14 +/- 0.9) X 10(4) calmodulin molecules per cell.

Na + /K + -pump is an electrogenic transmembrane ATPase located in the outer plasma membrane of cells. The Na + /K + -ATPase pumps 3 sodium ions out of cells while pumping 2 potassium ions into cells. Both cations move against their concentration gradients. This enzyme’s electrogenic nature means that it has a chronic role in stabilizing the resting membrane potential of the cell, in regulating the cell volume and in the signal transduction of the cell. This review will mainly consider the role of the Na + /K + -pump in neurons, with an emphasis on its role in modulating neurotransmitter receptor. Most of the literature on the modulation of neurotransmitter receptors refers to the situation in the mammalian nervous system, but the position is likely to be similar in most, if not all, invertebrate nervous systems.

Thalamocortical (TC) impulses potently influence the sensory neocortex, but the functional impact of individual TC neurons throughout the layers of the cortex has proved difficult to assess. Here we examine, in awake rabbits, the vertical distribution of monosynaptic currents generated in a somatosensory cortical "barrel" column by spontaneous impulses of single, topographically aligned TC neurons. We show that closely neighboring TC neurons generate widely differing patterns of monosynaptic activation within layers 4 and 6 of their aligned column. Moreover, synaptic currents generated by TC impulses with long preceding interspike intervals are greatly enhanced in both of these layers. The degree of this enhancement differs reliably among neighboring TC neurons but, for a given neuron, is very similar in layers 4 and 6. Our results indicate that in the awake state, TC synapses throughout the depth of the cortex serve as powerful filters of sensory information that reflect individual characteristics of their parent TC neuron.

This report includes the first sibling study of mouse behavior, and presents evidence for a heritable general cognitive ability (g) factor influencing cognitive batteries. Data from a population of male and female outbred mice (n = 84), and a replication study of male sibling pairs (n = 167) are reported. Arenas employed were the T-maze, the Morris water maze, the puzzle box, the Hebb-Williams maze, object exploration, a water plus-maze, and a second food-puzzle arena. The results show a factor structure consistent with the presence of g in mice. Employing one score per arena, this factor accounts for 41% of the variance in the first study (or 36% after sex regression) and 23% in the second, where this factor also showed sibling correlations of 0.17-0.21, which translates into an upper-limit heritability estimate of around 40%. Reliabilities of many tasks are low and consequently set an even lower ceiling for inter-arena or sibling correlations. Nevertheless, the factor structure is seen to remain fairly robust across permutations of the battery composition and the current findings fit well with other recent studies.

Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus, and spinal cord. In the immature hippocampus, the so-called "giant depolarizing potentials" (GDPs) are network-driven synaptic events generated by gamma-aminobutyric acid (GABA), which at this stage is depolarizing and excitatory. We have tested the hypothesis that during the first postnatal week, GDP-associated calcium signals may alter the properties of synaptic transmission at poorly developed mossy fiber (MF)-CA3 connections. We found that "pairing" GDPs with MF stimulation induced a persistent increase in synaptic efficacy at MF-CA3 synapses. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and disappeared. The potentiation depended on activation of voltage-dependent calcium channels and calcium flux. This activity may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit.

Oscillations of the local field potentials (LFPs) or electroencephalogram (EEG) at frequencies below 1 Hz are a hallmark of the slow-wave sleep. However, the timing of the underlying cellular events, which is an alternation of active and silent states of thalamocortical network, can be assessed only approximately from the phase of slow waves. Is it possible to detect, using the LFP or EEG, the timing of each episode of cellular activity or silence? With simultaneous recordings of the LFP and intracellular activity of 2-3 neocortical cells, we show that high-gamma-range (20-100 Hz) components in the LFP have significantly higher power when cortical cells are in active states as compared with silent-state periods. Exploiting this difference we have developed a new method, which uses the LFP signal to detect episodes of activity and silence of neocortical neurons. The method allows robust, reliable, and precise detection of timing of each episode of activity and silence of the neocortical network. It works with both surface and depth EEG, and its performance is affected little by the EEG prefiltering during recording. These results open new perspectives for studying differential operation of neural networks during periods of activity and silence, which rapidly alternate on the subsecond scale.

Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease-a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states.

Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

Using desensitized actomyosin from chicken gizzard smooth muscle, we found that the activity of actin-myosin interaction, as determined by superprecipitation, is controled by both myosin-and thin filament-linked dual mechanism. While Ca"-and calmodulin-dependent phosphorylation of myosin light chain by myosin light chain kinase was prerequisite for the actin-myosin interaction, calmodulin-and caldesmonlinked flip-flop mechanism served as an on-off switch for the actin-myosin interaction. Presence of tropomyosin in the system was essential for the proper interaction of actin and myosin. The present results in combination with the previous work (29) provide evidence that this flip-flop switch is controled by the concentration of Ca" in such a way that, at decreased Ca" levels, association of caldesmon with actin filament eliminates the actin-myosin interaction and, at increased Ca" levels, Ca"dependent association of calmodulin with caldesmon dissociates actin filament from caldesmon thus making actin filament available for the interaction with myosin. Thus, Ca" controls the actin-myosin interaction of gizzard muscle through both myosin-linked and thin filament-linked regulatory systems and the effects of Ca" on both regulatory systems are mediated by calmodulin.

We studied the effects of reversible cooling between 35 and 7 C on membrane properties and spike generation of cells in slices of rat visual cortex. Cooling led to a depolarization of the neurones and an increase of the input resistance, thus bringing the cells closer to spiking threshold. Excitability, measured with intracellular current steps, increased with cooling. Synaptic stimuli were most efficient in producing spikes at room temperature, but strong stimulation could evoke spikes even below 10 C. Spike width and total area increased with cooling, and spike amplitude was maximal between 12 and 20 C. Repetitive firing was enhanced in some cells by cooling to 20-25 C, but was always suppressed at lower temperatures. With cooling, passive potassium conductance decreased and the voltage-gated potassium current had a higher activation threshold and lower amplitude. At the same time, neither passive sodium conductance nor the activation threshold of voltage-dependent sodium channels changed. Therefore changing the temperature modifies the ratio between potassium and sodium conductances, and thus alters basic membrane properties. Data from two cells recorded in slices of cat visual cortex suggest a similar temperature dependence of the membrane properties of neocortical neurones to that described above in the rat. These results provide a framework for comparison of the data recorded at different temperatures, but also show the limitations of extending the conclusions drawn from in vitro data obtained at room temperature to physiological temperatures. Further, when cooling is used as an inactivation tool in vivo, it should be taken into account that the mechanism of inactivation is a depolarization block. Only a region cooled below 10 C is reliably silenced, but it is always surrounded by a domain of hyperexcitable cells.

Unit activities of the lateral geniculate body (LGB) were studied in free behaving cats during arousal, light sleep (sleep with high-voltage, slow EEG) and deep sleep (sleep with low-voltage, fast EEG). The LGB units were classified into two types according to their response patterns to stimulation of the optic chiasm and the visual cortex; by both types of stimulation the P units were fired singly at short latencies and the I units were fired repetitively at long latencies.1. Spontaneous activity of the P units changed markedly upon alternation of the behavioral state. During arousal the P units showed well-spaced regular discharges. During light sleep the grouped discharges consisting of 2-5 spikes became manifest intermingled with sporadic discharges. In deep sleep spontaneous activity was accelarated with occasional bursts of spikes (deep sleep bursts) lasting about 0.5 sec.2. The deep sleep waves of the LGB, which were mass activity of spiky form seen during deep sleep, were found to be correlated to the deep sleep burst of the P unit spontaneous activity in their negative phase. Suppression of the unit activity was seen during their positive phase.3. The rate of spontaneous activity of the P units was lowest during light sleep and increased from arousal to deep sleep.4. The firing probability of the P units to chiasmatic and visual cortical stimulation was lowest during light sleep and increased from arousal to deep sleep. This was true of the firing probability to the spontaneous synaptic bombardment.5. The I units did not alter significantly the rate of spontaneous activity and the strength of responsiveness to visual cortical stimulation when sleep changed from one type to another. Responsiveness of the I units to chiasmatic stimulation was higher during deep sleep than during light sleep, suggesting that orthodromic activation of the I units is mediated via the P units.