Short-wave Infrared Neural Stimulation Drives Graded Sciatic Nerve Activation Across A Continuum of Wavelengths.

Infrared neural stimulation (INS) is an optical stimulation technique which uses coherent light to stimulate nerves and neurons and which shows increased spatial selectivity compared to electrical stimulation. This could improve deep brain, high channel count, or vagus nerve stimulation. In this study, we seek to understand the wavelength dependence of INS in the near-infrared optical window. Rat sciatic nerves were excised ex vivo and stimulated with wavelengths between 700 and 900 nm. Recorded compound nerve action potentials (CNAPs) showed that stimulation was maximized in the 700 nm window despite comparable laser power levels across wavelengths. Computational models demonstrated that wavelength-based activation dependencies were not a result of passive optical properties. This data demonstrates that INS is both wavelength and power level dependent, which inform stimulation systems to actively target neural microcircuits in humans.

Interplay effects in highly modulated stereotactic body radiation therapy lung cases treated with volumetric modulated arc therapy.

Interplay effects in highly modulated stereotactic body radiation therapy lung cases treated with volumetric modulated arc therapy. PURPOSE: To evaluate the influence of tumor motion on dose delivery in highly modulated stereotactic body radiotherapy (SBRT) of lung cancer using volumetric modulated arc therapy (VMAT). METHODS: 4D-CT imaging data of the quasar respiratory phantom were acquired, using a GE Lightspeed 16-slice CT scanner, while the phantom reproduced patient specific respiratory traces. Flattening filter-free (FFF) dual-arc VMAT treatment plans were created on the acquired images in Pinnacle3 treatment planning system. Each plan was generated with varying levels of complexity characterized by the modulation complexity score. Static and dynamic measurements were delivered to GafChromic EBT3 film inside the respiratory phantom using an Elekta Versa HD linear accelerator. The treatment prescription was 10 Gy per fraction for 5 fractions. Comparisons of the planned and delivered dose distribution were performed using Radiological Imaging Technology (RIT) software. RESULTS: For the motion amplitudes and periods studied, the interplay effect is insignificant to the GTV coverage. The mean dose deviations between the planned and delivered dose distribution never went below -2.00% and a minimum dose difference of -5.05% was observed for a single fraction. However for amplitude of 2 cm, the dose error could be as large as 20.00% near the edges of the PTV at increased levels of complexity. Additionally, the modulation complexity score showed an ability to provide information related to dose delivery. A correlation value (R) of 0.65 was observed between the complexity score and the gamma passing rate for GTV coverage. CONCLUSIONS: As expected, respiratory motion effects are most evident for large amplitude respirations, complex fields, and small field margins. However, under all tested conditions target coverage was maintained.

An ultrasound based platform for image-guided radiotherapy in canine bladder cancer patients.

BACKGROUND AND PURPOSE: Ultrasound (US) is a non-invasive, non-radiographic imaging technique with high spatial and temporal resolution that can be used for localizing soft-tissue structures and tumors in real-time during radiotherapy (RT) (inter- and intra-fraction). A comprehensive approach incorporating an in-house 3D-US system within RT is presented. This system is easier to adopt into existing treatment protocols than current US based systems, with the aim of providing millimeter intra-fraction alignment errors and sensitivity to track intra-fraction bladder movement. MATERIALS AND METHODS: An in-house integrated US manipulator and platform was designed to relate the computed tomographic (CT) scanner, 3D-US and linear accelerator coordinate systems. An agar-based phantom with measured speed of sound and densities consistent with tissues surrounding the bladder was rotated (0-45°) and translated (up to 55 mm) relative to the US and CT coordinate systems to validate this device. After acquiring and integrating CT and US images into the treatment planning system, US-to-US and US-to-CT images were co-registered to re-align the phantom relative to the linear accelerator. RESULTS: Statistical errors from US-to-US registrations for various patient orientations ranged from 0.1 to 1.7 mm for x, y, and z translation components, and 0.0-1.1° for rotational components. Statistical errors from US-to-CT registrations were 0.3-1.2 mm for the x, y and z translational components and 0.1-2.5° for the rotational components. CONCLUSIONS: An ultrasound-based platform was designed, constructed and tested on a CT/US tissue-equivalent phantom to track bladder displacement with a statistical uncertainty to correct and track inter- and intra-fractional displacements of the bladder during radiation treatments.

Automated approach to detecting behavioral states using EEG-DABS.

Electrocorticographic (ECoG) signals represent cortical electrical dipoles generated by synchronous local field potentials that result from simultaneous firing of neurons at distinct frequencies (brain waves). Since different brain waves correlate to different behavioral states, ECoG signals presents a novel strategy to detect complex behaviors. We developed a program, EEG Detection Analysis for Behavioral States (EEG-DABS) that advances Fast Fourier Transforms through ECoG signals time series, separating it into (user defined) frequency bands and normalizes them to reduce variability. EEG-DABS determines events if segments of an experimental ECoG record have significantly different power bands than a selected control pattern of EEG. Events are identified at every epoch and frequency band and then are displayed as output graphs by the program. Certain patterns of events correspond to specific behaviors. Once a predetermined pattern was selected for a behavioral state, EEG-DABS correctly identified the desired behavioral event. The selection of frequency band combinations for detection of the behavior affects accuracy of the method. All instances of certain behaviors, such as freezing, were correctly identified from the event patterns generated with EEG-DABS. Detecting behaviors is typically achieved by visually discerning unique animal phenotypes, a process that is time consuming, unreliable, and subjective. EEG-DABS removes variability by using defined parameters of EEG/ECoG for a desired behavior over chronic recordings. EEG-DABS presents a simple and automated approach to quantify different behavioral states from ECoG signals.

Increased Expression of Epileptiform Spike/Wave Discharges One Year after Mild, Moderate, or Severe Fluid Percussion Brain Injury in Rats.

In this study, we describe increased expression of cortical epileptiform spike/wave discharges (SWD) in rats one year after mild, moderate, or severe fluid percussion traumatic brain injury (fpTBI). Groups of rats consisted of animals that had received mild, moderate, or severe fpTBI, or sham operation one year earlier than electrocorticography (ECoG) recordings. In addition, we included a group of age-matched naïve animals. ECoG was recorded from awake animals using epidural electrodes implanted on the injured hemisphere (right), sham-operated hemisphere (right), or right hemisphere in naïve animals. The SWDs were detected automatically using Fast Fourier Transformation and a novel algorithm for comparing changes in spectral power to control (nonepileptical) ECoG. The fpTBI resulted in increased expression of SWDs one year after injury compared with sham-operated or naïve animals. The number of SWD-containing ECoG epochs recorded in a 1 h recording session were: naïve 12.9 ± 10.3, n = 8, sham 23.6 ± 8.2, n = 10, mild TBI 78.9 ± 23.9, n = 10, moderate TBI 61.3 ± 32.5, n = 12, severe TBI 72.5 ± 28.3, n = 11 (mean ± standard error of the mean). Increased expression of SWDs was not related to injury severity. SWDs were observed to a lesser extent even in sham-operated and naïve animals. The data indicate that fpTBI exacerbates expression of SWDs in the rat and that this increase may be observed at least one year after injury. As others have discussed, the spontaneous occurrence of these epileptiform events in rodents limits the use of this model for investigations of acquired epilepsy, at least of the nonconvulsive type, after TBI.

The role of brachytherapy in the treatment of glioblastoma multiforme.

Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to deliver ionizing radiation directly into the tumor bed. Its application as a means to prolong survival in GBM patients over the past few decades has come with variable success. The objective of this review is to describe the utility of BT in GBM, and to report the outcomes and adverse events associated with its use in different multimodal treatment approaches. A search of the literature was conducted using the PubMed database. The most recent search was performed in September 2015. Thirty-two series involving 1571 patients were included in our review. The longest median overall survival (MOS) following BT for newly diagnosed GBM reached 28.5 months. Overall, 1-, 2-, and 3-year survival rates were 46-89 %, 20-57 %, and 14-27 %. For recurrent GBM, the longest reported MOS after BT was 15.9 months. One-, 2- and 3-year survival rates for recurrent GBM were 10-66 %, 3-23 %, and 9-15 %. Adverse events were reported in 27 % of patients. Reoperation for radiation necrosis occurred in 4 and 27 % of patients following low- and high-dose rate BT, respectively. BT is a feasible option for extending survival in carefully selected GBM patients. As patient outcomes and overall survival improve with more aggressive radiotherapy, so does the risk of radiation-related complications. The most effective use of BT is likely as a part of multimodal treatment with other novel therapies.

EEGgui: a program used to detect electroencephalogram anomalies after traumatic brain injury.

BACKGROUND: Identifying and quantifying pathological changes in brain electrical activity is important for investigations of brain injury and neurological disease. An example is the development of epilepsy, a secondary consequence of traumatic brain injury. While certain epileptiform events can be identified visually from electroencephalographic (EEG) or electrocorticographic (ECoG) records, quantification of these pathological events has proved to be more difficult. In this study we developed MATLAB-based software that would assist detection of pathological brain electrical activity following traumatic brain injury (TBI) and present our MATLAB code used for the analysis of the ECoG. METHODS: Software was developed using MATLAB(™) and features of the open access EEGLAB. EEGgui is a graphical user interface in the MATLAB programming platform that allows scientists who are not proficient in computer programming to perform a number of elaborate analyses on ECoG signals. The different analyses include Power Spectral Density (PSD), Short Time Fourier analysis and Spectral Entropy (SE). ECoG records used for demonstration of this software were derived from rats that had undergone traumatic brain injury one year earlier. RESULTS: The software provided in this report provides a graphical user interface for displaying ECoG activity and calculating normalized power density using fast fourier transform of the major brain wave frequencies (Delta, Theta, Alpha, Beta1, Beta2 and Gamma). The software further detects events in which power density for these frequency bands exceeds normal ECoG by more than 4 standard deviations. We found that epileptic events could be identified and distinguished from a variety of ECoG phenomena associated with normal changes in behavior. We further found that analysis of spectral entropy was less effective in distinguishing epileptic from normal changes in ECoG activity. CONCLUSION: The software presented here was a successful modification of EEGLAB in the Matlab environment that allows detection of epileptiform ECoG signals in animals after TBI. The code allows import of large EEG or ECoG data records as standard text files and uses fast fourier transform as a basis for detection of abnormal events. The software can also be used to monitor injury-induced changes in spectral entropy if required. We hope that the software will be useful for other investigators in the field of traumatic brain injury and will stimulate future advances of quantitative analysis of brain electrical activity after neurological injury or disease.

Chronic nicotine exposure inhibits estrogen-mediated synaptic functions in hippocampus of female rats.

Nicotine, the addictive agent in cigarettes, reduces circulating estradiol-17ß (E2) and inhibits E2-mediated intracellular signaling in hippocampus of female rats. In hippocampus, E2-signaling regulates synaptic plasticity by phosphorylation of the N-methyl-D-aspartic acid receptor subunit NR2B and cyclic-AMP response element binding protein (pCREB). Therefore, we hypothesized that chronic nicotine exposure induces synaptic dysfunction in hippocampus of female rats. Female rats were exposed to nicotine or saline for 16 days followed by electrophysiological analysis of hippocampus. Briefly, population measurements of excitatory post-synaptic field potentials (fEPSPs) were recorded from stratum radiatum of the CA1 hippocampal slice subfield. A strict software-controlled protocol was used which recorded 30 min of baseline data (stimulation rate of 1/min), a paired-pulse stimulation sequence followed by tetanic stimulation, and 1h of post-tetanus recording. EPSP amplitude and the initial EPSP slope were measured off-line. We then investigated by Western blot analysis the effects of nicotine on hippocampal estrogen receptor-beta (ER-ß), NR2B and pCREB. The results demonstrated significantly decreased post-tetanic potentiation and paired-pulse facilitation at the 40, and 80 ms interval in nicotine-exposed rats compared to the saline group. Western blot analysis revealed that nicotine decreased protein levels of ER-ß, NR2B, and pCREB. We also confirmed the role of E2 in regulating NR2B and pCREB phosphorylation by performing Western blots in hippocapmal tissue obtained from E2-treated ovariectomized rats. In conclusion, chronic nicotine exposure attenuates short-term synaptic plasticity, and the observed synaptic defects might be a consequence of loss of estradiol-17ß-signaling. However, determining the exact molecular mechanisms of chronic nicotine exposure on synaptic plasticity specific to the female brain require further investigation.

EphrinBs regulate D-serine synthesis and release in astrocytes.

There is growing evidence that astrocytes play critical roles in neuron-glial interactions at the synapse. Astrocytes are believed to regulate presynaptic and postsynaptic structures and functions, in part, by the release of gliotransmitters such as glutamate, ATP, and d-serine; however, little is known of how neurons and astrocytes communicate to regulate these processes. Here, we investigated a family of transmembrane proteins called ephrinBs and Eph receptors that are expressed in the synapse and are known to regulate synaptic transmission and plasticity. In addition to their presence on CA1 hippocampal neurons, we determined that ephrins and Eph receptors are also expressed on hippocampal astrocytes. Stimulation of hippocampal astrocytes with soluble ephrinB3, known to be expressed on CA1 postsynaptic dendrites, enhanced d-serine synthesis and release in culture. Conversely, ephrinB3 had no effect on d-serine release from astrocytes deficient in EphB3 and EphA4, which are the primary receptors for ephrinB3. Eph receptors mediate this response through interactions with PICK1 (protein interacting with C-kinase) and by dephosphorylating protein kinase C α to activate the conversion of l-serine to d-serine by serine racemase. These findings are supported in vivo, where reduced d-serine levels and synaptic transmissions are observed in the absence of EphB3 and EphA4. These data support a role for ephrins and Eph receptors in regulating astrocyte gliotransmitters, which may have important implications on synaptic transmission and plasticity.