Estimating The Reliability of the Lawrence Livermore National Laboratory (LLNL) Flash X-ray (FXR) Machine

At Lawrence Livermore National Laboratory (LLNL), our flash X-ray accelerator (FXR) is used on multi-million dollar hydrodynamic experiments. Because of the importance of the radiographs, FXR must be ultra-reliable. Flash linear accelerators that can generate a 3 kA beam at 18 MeV are very complex. They have thousands, if not millions, of critical components that could prevent the machine from performing correctly. For the last five years, we have quantified and are tracking component failures. From this data, we have determined that the reliability of the high-voltage gas-switches that initiate the pulses, which drive the accelerator cells, dominates the statistics. The failure mode is a single-switch pre-fire that reduces the energy of the beam and degrades the X-ray spot-size. The unfortunate result is a lower resolution radiograph. FXR is a production machine that allows only a modest number of pulses for testing. Therefore, reliability switch testing that requires thousands of shots is performed on our test stand. Study of representative switches has produced pre-fire statistical information and probability distribution curves. This information is applied to FXR to develop test procedures and determine individual switch reliability using a minimal number of accelerator pulses

Consistency and diversity of spike dynamics in the neurons of bed nucleus of Stria Terminalis of the rat: a dynamic clamp study

Neurons display a high degree of variability and diversity in the expression and regulation of their voltage-dependent ionic channels. Under low level of synaptic background a number of physiologically distinct cell types can be identified in most brain areas that display different responses to standard forms of intracellular current stimulation. Nevertheless, it is not well understood how biophysically different neurons process synaptic inputs in natural conditions, i.e., when experiencing intense synaptic bombardment in vivo. While distinct cell types might process synaptic inputs into different patterns of action potentials representing specific "motifs'' of network activity, standard methods of electrophysiology are not well suited to resolve such questions. In the current paper we performed dynamic clamp experiments with simulated synaptic inputs that were presented to three types of neurons in the juxtacapsular bed nucleus of stria terminalis (jcBNST) of the rat. Our analysis on the temporal structure of firing showed that the three types of jcBNST neurons did not produce qualitatively different spike responses under identical patterns of input. However, we observed consistent, cell type dependent variations in the fine structure of firing, at the level of single spikes. At the millisecond resolution structure of firing we found high degree of diversity across the entire spectrum of neurons irrespective of their type. Additionally, we identified a new cell type with intrinsic oscillatory properties that produced a rhythmic and regular firing under synaptic stimulation that distinguishes it from the previously described jcBNST cell types. Our findings suggest a sophisticated, cell type dependent regulation of spike dynamics of neurons when experiencing a complex synaptic background. The high degree of their dynamical diversity has implications to their cooperative dynamics and synchronization

Design of a High Field Stress, Velvet Cathode for the Flash X-Ray (FXR) Induction Accelerator

A new cathode design has been proposed for the Flash X-Ray (FXR) induction linear accelerator with the goal of lowering the beam emittance. The original design uses a conventional Pierce geometry and applies a peak field of 134 kV/cm (no beam) to the velvet emission surface. Voltage/current measurements indicate that the velvet begins emitting near this peak field value and images of the cathode show a very non-uniform distribution of plasma light. The new design has a flat cathode/shroud profile that allows for a peak field stress of 230 kV/cm on the velvet. The emission area is reduced by about a factor of four to generate the same total current due to the greater field stress. The relatively fast acceleration of the beam, approximately 2.5 MeV in 10 cm, reduces space charge forces that tend to hollow the beam for a flat, non-Pierce geometry. The higher field stress achieved with the same rise time is expected to lead to an earlier and more uniform plasma formation over the velvet surface. Simulations and initial testing are presented

Flash X-Ray (Fxr) Linear Induction Accelerator (Lia) Optimization Sensor Delay Correction

The radiographic goal of the FXR Optimization Project is to generate an x-ray pulse with peak energy of 19 MeV, spot-size of 1.5 mm, a dose of 500 rad, and duration of 60 ns. The electrical objectives are to generate a 3 kA electron-beam and refine our 16 MV accelerator so that the voltage does not vary more than 1%-rms. In a multi-cell linear induction accelerator, like FXR, the timing of the acceleration pulses relative to the beam is critical. The pulses must be timed optimally so that a cell is at full voltage before the beam arrives and does not drop until the beam passes. In order to stay within the energy-variation budget, the synchronization between the cells and beam arrival must be controlled to a couple of nanoseconds. Therefore, temporal measurements must be accurate to a fraction of a nanosecond. FXR Optimization Project developed a one-giga-sample per second (gs/s) data acquisition system to record beam sensor data. Signal processing algorithms were written to determine cell timing with an uncertainty of a fraction of a nanosecond. However, the uncertainty in the sensor delay was still a few nanoseconds. This error had to be reduced if we are to improve the quality of the electron beam. Two types of sensors are used to align the cell voltage pulse against the beam current. The beam current is measured with resistive-wall sensors. The cell voltages are read with capacitive voltage monitors. Sensor delays can be traced to two mechanisms: (1) the sensors are not co-located at the beam and cell interaction points, and (2) the sensors have different length jumper cables and other components that connect them to the standard-length coaxial cables of the data acquisition system. Using the physical locations and dimensions of the sensor components, and the dielectric constant of the materials, delay times were computed. Relative to the cell voltage, the beam current was theoretically reporting late by 7.7 ns. Two experiments were performed to verify and refine the sensor delay correction. In the first experiment, the beam was allowed to drift through a cell that was not pulsed. The beam induces a potential into the cell that is read by the voltage monitor. Analysis of the data indicated that the beam sensor signal was likely 7.1 ns late. In the second experiment, the beam current is calculated from the injector diode voltage that is the sum of the cell voltages. A 7 ns correction produced a very good match between the signals from the two types of sensors. For simplicity, we selected a correction factor that advanced the current signals by 7 ns. This should reduce the uncertainty in the temporal measurements to less than 1 ns

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Key Modulatory Role of Presynaptic Adenosine A 2A

Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders

Long-term impact of four different strategies for delivering an on-line curriculum about herbs and other dietary supplements

BACKGROUND: Previous research has shown that internet education can lead to short-term improvements in clinicians' knowledge, confidence and communication practices. We wished to better understand the duration of these improvements and whether different curriculum delivery strategies differed in affecting these improvements. METHODS: As previously described, we conducted a randomized control trial comparing four different strategies for delivering an e-curriculum about herbs and other dietary supplements (HDS) to clinicians. The four strategies were delivering the curriculum by: a) email over 10 weeks; b) email within one week; c) web-site over 10 weeks; d) web-site within one week. Participants were surveyed at baseline, immediately after the course and 6–10 months after completing the course (long-term). Long-term outcomes focused on clinicians' knowledge, confidence and communication practices. RESULTS: Of the 780 clinicians who completed the course, 385 (49%) completed the long-term survey. Completers and non-completers of the long-term survey had similar demographics and professional characteristics at baseline. There were statistically significant improvements from baseline to long-term follow-up in knowledge, confidence and communication practices; these improvements did not differ by curriculum delivery strategy. Knowledge scores improved from 67.7 ± 10.3 at baseline to 78.8 ± 12.3 at long-term follow-up (P < 0.001). Confidence scores improved from 53.7 ± 17.8 at baseline to 66.9 ± 12.0 at long term follow-up (P < 0.001); communication scores improved from 2.6 ± 1.9 at baseline to 3.6 ± 2.1 (P < 0.001) at long-term follow-up. CONCLUSION: This e- curriculum led to significant and sustained improvements in clinicians' expertise about HDS regardless of the delivery strategy. Future studies should compare the impact of required vs. elective courses and self-reported vs. objective measures of behavior change

Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity

Endocannabinoids Generated by Ca2+ or by Metabotropic Glutamate Receptors Appear to Arise from Different Pools of Diacylglycerol Lipase

The identity and subcellular sources of endocannabinoids (eCBs) will shape their ability to affect synaptic transmission and, ultimately, behavior. Recent discoveries support the conclusion that 2-arachidonoyl glycerol, 2-AG, is the major signaling eCB, however, some important issues remain open. 2-AG can be synthesized by a mechanism that is strictly Ca2+-dependent, and another that is initiated by G-protein coupled receptors (GPCRs) and facilitated by Ca2+. An important question is whether or not the 2-AG in these cases is synthesized by the same pool of diacylglycerol lipase alpha (DAGLα). Using whole-cell voltage-clamp techniques in CA1 pyramidal cells in acute in vitro rat hippocampal slices, we investigated two mechanistically distinct eCB-mediated responses to address this issue. We now report that pharmacological inhibitors of DGLα have quantitatively different effects on eCB-mediated responses triggered by different stimuli, suggesting that functional, and perhaps physical, distinctions among pools of DAGLα exist