Quantitative functional imaging of the pigeon brain: implications for the evolution of avian powered flight.

The evolution of flight is a rare event in vertebrate history, and one that demands functional integration across multiple anatomical/physiological systems. The neuroanatomical basis for such integration and the role that brain evolution assumes in behavioural transformations remain poorly understood. We make progress by (i) generating a positron emission tomography (PET)-based map of brain activity for pigeons during rest and flight, (ii) using these maps in a functional analysis of the brain during flight, and (iii) interpreting these data within a macroevolutionary context shaped by non-avian dinosaurs. Although neural activity is generally conserved from rest to flight, we found significant increases in the cerebellum as a whole and optic flow pathways. Conserved activity suggests processing of self-movement and image stabilization are critical when a bird takes to the air, while increased visual and cerebellar activity reflects the importance of integrating multimodal sensory information for flight-related movements. A derived cerebellar capability likely arose at the base of maniraptoran dinosaurs, where volumetric expansion and possible folding directly preceded paravian flight. These data represent an important step toward establishing how the brain of modern birds supports their unique behavioural repertoire and provide novel insights into the neurobiology of the bird-like dinosaurs that first achieved powered flight.

Proton Bragg Peak FLASH Enables Organ Sparing and Ultra-High Dose-Rate Delivery: Proof of Principle in Recurrent Head and Neck Cancer.

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90-100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.

Implementation of novel measurement-based patient-specific QA for pencil beam scanning proton FLASH radiotherapy.

BACKGROUND: Several studies have shown pencil beam scanning (PBS) proton therapy is a feasible and safe modality to deliver conformal and ultra-high dose rate (UHDR) FLASH radiation therapy. However, it would be challenging and burdensome to conduct the quality assurance (QA) of the dose rate along with conventional patient-specific QA (psQA). PURPOSE: To demonstrate a novel measurement-based psQA program for UHDR PBS proton transmission FLASH radiotherapy (FLASH-RT) using a high spatiotemporal resolution 2D strip ionization chamber array (SICA). METHODS: The SICA is a newly designed open-air strip-segmented parallel plate ionization chamber, which is capable of measuring spot position and profile through 2 mm-spacing-strip electrodes at a 20 kHz sampling rate (50 µs per event) and has been characterized to exhibit excellent dose and dose rate linearity under UHDR conditions. A SICA-based delivery log was collected for each irradiation containing the measured position, size, dwell time, and delivered MU for each planned spot. Such spot-level information was compared with the corresponding quantities in the treatment planning system (TPS). The dose and dose rate distributions were reconstructed on patient CT using the measured SICA log and compared to the planned values in volume histograms and 3D gamma analysis. Furthermore, the 2D dose and dose rate measurements were compared with the TPS calculations of the same depth. In addition, simulations using different machine-delivery uncertainties were performed, and QA tolerances were deduced. RESULTS: A transmission proton plan of 250 MeV for a lung lesion was planned and measured in a dedicated ProBeam research beamline (Varian Medical System) with a nozzle beam current between 100 to 215 nA. The worst gamma passing rates for dose and dose rate of the 2D SICA measurements (four fields) compared to TPS prediction (3%/3 mm criterion) were 96.6% and 98.8%, respectively, whereas the SICA-log reconstructed 3D dose distribution achieved a gamma passing rate of 99.1% (2%/2 mm criterion) compared to TPS. The deviations between SICA measured log, and TPS were within 0.3 ms for spot dwell time with a mean difference of 0.069 ± 0.11 s, within 0.2 mm for spot position with a mean difference of -0.016 ± 0.03 mm in the x-direction, and -0.036 ± 0.059 mm in the y-direction, and within 3% for delivered spot MUs. Volume histogram metric of dose (D95) and dose rate (V40Gy/s ) showed minimal differences, within less than 1%. CONCLUSIONS: This work is the first to describe and validate an all-in-one measurement-based psQA framework that can fulfill the goals of validating the dose rate accuracy in addition to dosimetric accuracy for proton PBS transmission FLASH-RT. The successful implementation of this novel QA program can provide future clinical practice with more confidence in the FLASH application.

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-compatible PET System.

In this study, we used a compact, high-resolution, and MRI-compatible PET camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

Dose rate and dose robustness for proton transmission FLASH-RT treatment in lung cancer.

Purposes: To evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment. Methods and materials: An in-house FLASH planning platform was used to optimize 10 lung cancer patients previously consecutively treated with proton stereotactic body radiation therapy (SBRT) to receive 3 and 5 transmission beams (Trx-3fds and Trx-5fds, respectively) to 34 Gy in a single fraction. Perturbation scenarios (n=12) for setup and range uncertainties (5 mm and 3.5%) were introduced, and dose-volume histogram and dose-rate-volume histogram bands were generated. Conventional proton SBRT clinical plans were used as a reference. RTOG 0915 dose metrics and 40 Gy/s dose rate coverage (V40Gy/s) were used to assess the dose and dose rate robustness. Results: Trx-5fds yields a comparable iCTV D2% of 105.3%, whereas Trx-3fds resulted in inferior D2% of 111.9% to the clinical SBRT plans with D2% of 105.6% (p<0.05). Both Trx-5fds and Trx-3fds plans had slightly worse dose metrics to organs at risk than SBRT plans. Trx-5fds achieved superior dosimetry robustness for iCTV, esophagus, and spinal cord doses than both Trx-3fds and conventional SBRT plans. There was no significant difference in dose rate robustness for V40Gy/s coverage between Trx-3fds and Trx-5fds. Dose rate distribution has similar distributions to the dose when perturbation exists. Conclusion: Transmission plans yield overall modestly inferior plan quality compared to the conventional proton SBRT plans but provide improved robustness and the potential for a toxicity-sparing FLASH effect. By using more beams (5- versus 3-field), both dose and dose rate robustness for transmission plans can be achieved.

Use of single-energy proton pencil beam scanning Bragg peak for intensity-modulated proton therapy FLASH treatment planning in liver-hypofractionated radiation therapy.

PURPOSE: The transmission proton FLASH technique delivers high doses to the normal tissue distal to the target, which is less conformal compared to the Bragg peak technique. To investigate FLASH radiotherapy (RT) planning using single-energy Bragg peak beams with a similar beam arrangement as clinical intensity-modulated proton therapy (IMPT) in a liver stereotactic body radiation therapy (SBRT) and to characterize the plan quality, dose sparing of organs-at-risk (OARs), and FLASH dose rate percentage. MATERIALS AND METHODS: An in-house platform was developed to enable inverse IMPT-FLASH planning using single-energy Bragg peaks. A universal range shifter and range compensators were utilized to effectively align the Bragg peak to the distal edge of the target. Two different minimum MU settings of 400 and 800 MU/spot (Bragg-400 MU and Bragg-800 MU) plans were investigated on 10 consecutive hepatocellular carcinoma patients previously treated by IMPT-SBRT to evaluate the FLASH dose and dose rate coverage for OARs. The IMPT-FLASH using single-energy Bragg peaks delivered 50 Gy in five fractions with similar or identical beam arrangement to the clinical IMPT-SBRT plans. NRG GI003 dose constraint metrics were used. Three dose rate calculation methods, including average dose rate (ADR), dose threshold dose rate (DTDR), and dose-ADR (DADR), were all studied. RESULTS: The novel spot map optimization can fulfill the inverse planning using single-energy Bragg peaks. All the Bragg peak FLASH plans achieved similar results for the liver-gross tumor volume (GTV) Dmean and heart D 0.5 c m 3 ${D_{0.5\,{\rm{c}}{{\rm{m}}^3}}}$ , compared to SBRT-IMPT. The Bragg-800 MU plans resulted in 18.3% higher clinical target volume (CTV) D 2 c m 3 ${D_{2\,{\rm{c}}{{\rm{m}}^{\rm{3}}}}}$ compared with SBRT (p < 0.05), and no significant difference was found between Bragg-400 MU and SBRT plans. For the CTV Dmax , SBRT plans resulted in 10.3% (p < 0.01) less than Bragg-400 MU plans and 16.6% (p < 0.01) less than Bragg-800 MU plans. The Bragg-800 MU plans generally achieved higher ADR, DADR, and DTDR dose rates than Bragg-400 MU plans, and DADR mostly led to the highest V40 Gy/s compared to other dose rate calculation methods, whereas ADR led to the lowest. The lower dose rate portions in certain OARs are related to the lower dose deposited due to the farther distances from targets, especially in the penumbra of the beams. CONCLUSION: Single-energy Bragg peak IMPT-FLASH plans eliminate the exit dose in normal tissues, maintaining comparable dose metrics to the conventional IMPT-SBRT plans, while achieving a sufficient FLASH dose rate for liver cancers. This study demonstrates the feasibility of and sufficiently high dose rate when applying the Bragg peak FLASH treatment for a liver cancer hypofractionated FLASH therapy. The advancement of this novel method has the potential to optimize treatment for liver cancer patients.

Advanced pencil beam scanning Bragg peak FLASH-RT delivery technique can enhance lung cancer planning treatment outcomes compared to conventional multiple-energy proton PBS techniques.

PURPOSE: To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application. METHODS: Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34 Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V40Gy/s) were calculated as a metric of the FLASH-sparing effect. RESULTS: For higher dose thresholds, the Bragg peak plans achieved greater V40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were > 5 Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D2%(%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p < 0.01) and that of Bragg peak 1200 MU plans of 115.95% (p < 0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p > 0.05). CONCLUSION: Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques.

A Universal Range Shifter and Range Compensator Can Enable Proton Pencil Beam Scanning Single-Energy Bragg Peak FLASH-RT Treatment Using Current Commercially Available Proton Systems.

PURPOSE: Transmission beams have been proposed for ultra-high dose (or FLASH) proton planning, limiting the organ sparing potentials of proton therapy. By pulling back the ranges of the highest energy proton beams and compensating proton ranges to adapt to the target distally, the exit dose of proton beams can be eliminated to better protect organs at risk while still preserving FLASH dose rate delivery. METHOD AND MATERIALS: An inverse planning tool was developed to optimize intensity modulated proton therapy using a single-energy layer for FLASH radiation therapy planning. The range pull-backs were calculated to stop single-energy proton beams at the distal edge of the target. The spot map and weights of each field were optimized to achieve a sufficient dose rate using proton beam Bragg peaks. A C-shape target in phantom, along with 6 consecutive lung cancer patients previously treated using proton stereotactic body radiation therapy were planned using this novel Bragg Peak method and also transmission technique. Dosimetry characteristics and 3-dimensional dose rate were investigated. RESULTS: The minimum monitor units (MU) for transmission and Bragg peak plans were 400 MU/spot and 1200 MU/spot, respectively, corresponding to spot peak dose rates of 670 GyRBE (relative biological effectiveness) per second and 1950 GyRBE per second. Bragg peak plans yield a generally comparable target uniformity while significantly reducing dose spillage volume from the low to medium dose level. For all the 6 lung cases delivery of 34 GyRBE in 1 fraction, assessing Radiation Therapy Oncology Group 0915 constraints, the lung V7GyRBE volume was reduced by up to 32% (P = .001) for Bragg peak plans. The transmission plans tended to generate 2.4% higher FLASH dose rate coverage (V40GyRBE/s) versus Bragg peak plans over the major organs at risk. However, Bragg peak plans could also reach the FLASH radiation therapy threshold of V40GyRBE/s using a higher MU/spot and sophisticated dose-rate optimization algorithm. CONCLUSIONS: This first proof-of-concept study has demonstrated this novel method of combining range pull-back and powerful inverse optimization capable of achieving FLASH dose rate based on currently available machine parameters using a single-energy Bragg peak. Similar target coverage and uniformity can be maintained by Bragg peak FLASH plans while substantially improving the sparing of organs at risk compared with transmission plans.

A Novel Proton Pencil Beam Scanning FLASH RT Delivery Method Enables Optimal OAR Sparing and Ultra-High Dose Rate Delivery: A Comprehensive Dosimetry Study for Lung Tumors.

PURPOSE: While transmission proton beams have been demonstrated to achieve ultra-high dose rate FLASH therapy delivery, they are unable to spare normal tissues distal to the target. This study aims to compare FLASH treatment planning using single energy Bragg peak proton beams versus transmission proton beams in lung tumors and to evaluate Bragg peak plan optimization, characterize plan quality, and quantify organ-at-risk (OAR) sparing. MATERIALS AND METHODS: Both Bragg peak and transmission plans were optimized using an in-house platform for 10 consecutive lung patients previously treated with proton stereotactic body radiation therapy (SBRT). To bring the dose rate up to the FLASH-RT threshold, Bragg peak plans with a minimum MU/spot of 1200 and transmission plans with a minimum MU/spot of 400 were developed. Two common prescriptions, 34 Gy in 1 fraction and 54 Gy in 3 fractions, were studied with the same beam arrangement for both Bragg peak and transmission plans (n = 40 plans). RTOG 0915 dosimetry metrics and dose rate metrics based on different dose rate calculations, including average dose rate (ADR), dose-averaged dose rate (DADR), and dose threshold dose rate (DTDR), were investigated. We then evaluated the effect of beam angular optimization on the Bragg peak plans to explore the potential for superior OAR sparing. RESULTS: Bragg peak plans significantly reduced doses to several OAR dose parameters, including lung V7.4Gy and V7Gy by 32.0% (p < 0.01) and 30.4% (p < 0.01) for 34Gy/fx plans, respectively; and by 40.8% (p < 0.01) and 41.2% (p < 0.01) for 18Gy/fx plans, respectively, compared with transmission plans. Bragg peak plans have ~3% less in DADR and ~10% differences in mean OARs in DTDR and DADR relative to transmission plans due to the larger portion of lower dose regions of Bragg peak plans. With angular optimization, optimized Bragg peak plans can further reduce the lung V7Gy by 20.7% (p < 0.01) and V7.4Gy by 19.7% (p < 0.01) compared with Bragg peak plans without angular optimization while achieving a similar 3D dose rate distribution. CONCLUSION: The single-energy Bragg peak plans achieve superior dosimetry performances in OARs to transmission plans with comparable dose rate performances for lung cancer FLASH therapy. Beam angle optimization can further improve the OAR dosimetry parameters with similar 3D FLASH dose rate coverage.

Quantitative Assessment of 3D Dose Rate for Proton Pencil Beam Scanning FLASH Radiotherapy and Its Application for Lung Hypofractionation Treatment Planning.

To quantitatively assess target and organs-at-risk (OAR) dose rate based on three proposed proton PBS dose rate metrics and study FLASH intensity-modulated proton therapy (IMPT) treatment planning using transmission beams. An in-house FLASH planning platform was developed to optimize transmission (shoot-through) plans for nine consecutive lung cancer patients previously planned with proton SBRT. Dose and dose rate calculation codes were developed to quantify three types of dose rate calculation methods (dose-averaged dose rate (DADR), average dose rate (ADR), and dose-threshold dose rate (DTDR)) based on both phantom and patient treatment plans. Two different minimum MU/spot settings were used to optimize two different dose regimes, 34-Gy in one fraction and 45-Gy in three fractions. The OAR sparing and target coverage can be optimized with good uniformity (hotspot < 110% of prescription dose). ADR, accounting for the spot dwelling and scanning time, gives the lowest dose rate; DTDR, not considering this time but a dose-threshold, gives an intermediate dose rate, whereas DADR gives the highest dose rate without considering any time or dose-threshold. All three dose rates attenuate along the beam direction, and the highest dose rate regions often occur on the field edge for ADR and DTDR, whereas DADR has a better dose rate uniformity. The differences in dose rate metrics have led a large variation for OARs dose rate assessment, posing challenges to FLASH clinical implementation. This is the first attempt to study the impact of the dose rate models, and more investigations and evidence for the details of proton PBS FLASH parameters are needed to explore the correlation between FLASH efficacy and the dose rate metrics.

FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification.

PURPOSE: This work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode. METHODS AND MATERIALS: An in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s). RESULTS: All plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans. CONCLUSION: This is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.

Evaluation of quantitative, efficient image reconstruction for VersaPET, a compact PET system.

PURPOSE: Previously we developed a high-resolution positron emission tomography (PET) system-VersaPET-characterized by a block geometry with relatively large axial and transaxial interblock gaps and a compact geometry susceptible to parallax blurring effects. In this work, we report the qualitative and quantitative evaluation of a graphic processing unit (GPU)-accelerated maximum-likelihood by expectation-maximization (MLEM) image reconstruction framework for VersaPET which features accurate system geometry and projection space point-spread-function (PSF) modeling. METHODS: We combined the ray-tracing module from software for tomographic image reconstruction (STIR), an open-source PET image reconstruction package, with VersaPET's exact block geometry for the geometric system matrix. Point-spread-function modeling of crystal penetration and scattering was achieved by a custom Monte-Carlo simulation for projection space blurring in all dimensions. We also parallelized the reconstruction in GPU taking advantage of the system's symmetry for PSF computation. To investigate the effects of PSF width, we generated and studied multiple kernels between one that reflects the true LYSO density in the MC simulation and another that reflects geometry only (no PSF). GATE simulations of hot and cold-sphere phantoms with spheres of different sizes, real microDerenzo phantom, and human blood vessel data were used to characterize the quantitative and qualitative performances of the reconstruction. RESULTS: Reconstruction with an accurate system geometry effectively improved image quality compared to STIR (version 3.0) which assumes an idealized system geometry. Reconstructions of GATE-simulated hot-sphere phantom data showed that all PSF kernels achieved superior performance in contrast recovery and bias reduction compared to using no PSF, but may introduce edge artifact and lumped background noise pattern depending on the width of PSF kernels. Cold-sphere phantom simulation results also indicated improvement in contrast recovery and quantification with PSF modeling (compared to no PSF) for 5 and 10 mm cold spheres. Real microDerenzo phantom images with the PSF kernel that reflects the true LYSO density showed degraded resolving power of small sectors that could be resolved more clearly by underestimated PSF kernels, which is consistent with recent literature despite differences in scanner geometries and in approaches to system model estimation. The human vessel results resemble those of the hot-sphere phantom simulation with the PSF kernel that reflects the true LYSO density achieving the highest peak in the time activity curve (TAC) and similar lumped noise pattern. CONCLUSIONS: We fully evaluated a practical MLEM reconstruction framework that we developed for VersaPET in terms of qualitative and quantitative performance. Different PSF kernels may be adopted for improving the results of specific imaging tasks but the underlying reasons for the variation in optimal kernel for the real and simulation studies requires further study.

Behavioral neuroimaging in birds using PET.

BACKGROUND: Birds comprise the most diverse group of terrestrial vertebrates. This success likely is related to the evolution of powered flight over 75 mya. Modern approaches for studying brain function, however, have yet to be fully adapted and applied to birds, especially as they relate to specific behaviors including flight. New method: We have developed a comprehensive set of in vivo experimental methods utilizing PET imaging with F-18 labeled fluorodeoxyglucose (FDG) to study regional changes in metabolism specifically related to flight, yet applicable to other behaviors as well. It incorporates approaches for selection of species, behavioral/imaging paradigm, animal preparation, radiotracer injection route, image quantification, and image analysis via an enhanced brain atlas. We also carried out preliminary modeling studies to better understand tracer kinetics. RESULTS: The methods were successful in identifying brain regions statistically associated with flight using only 8 animals. Peak brain uptake of FDG between birds and rodents is similar despite much higher blood glucose levels in birds. We also confirmed that brain uptake of FDG steadily decreases after the initial peak and provide evidence that it may be related to greater dephosphorylation of FDG phosphate than that observed in mammals. Comparison with existing methods: FDG PET has been used in only a few studies of the bird brain. We introduce a new species, more realistic flight behavior, paired (test/retest) design, and improved quantification and analysis approaches. CONCLUSIONS: The proposed imaging protocol is non-invasive yet sensitive to regional metabolic changes in the bird brain related to behavior.

A compact high resolution flat panel PET detector based on the new 4-side buttable MPPC for biomedical applications.

Compact high-resolution panel detectors using virtual pinhole (VP) PET geometry can be inserted into existing clinical or pre-clinical PET systems to improve regional spatial resolution and sensitivity. Here we describe a compact panel PET detector built using the new Though Silicon Via (TSV) multi-pixel photon counters (MPPC) detector. This insert provides high spatial resolution and good timing performance for multiple bio-medical applications. Because the TSV MPPC design eliminates wire bonding and has a package dimension which is very close to the MPPC's active area, it is 4-side buttable. The custom designed MPPC array (based on Hamamatsu S12641-PA-50(x)) used in the prototype is composed of 4 × 4 TSV-MPPC cells with a 4.46 mm pitch in both directions. The detector module has 16 × 16 lutetium yttrium oxyorthosilicate (LYSO) crystal array, with each crystal measuring 0.92 × 0.92 × 3 mm3 with 1.0 mm pitch. The outer diameter of the detector block is 16.8 × 16.8 mm2. Thirty-two such blocks will be arranged in a 4 × 8 array with 1 mm gaps to form a panel detector with detection area around 7 cm × 14 cm in the full-size detector. The flood histogram acquired with Ge-68 source showed excellent crystal separation capability with all 256 crystals clearly resolved. The detector module's mean, standard deviation, minimum (best) and maximum (worst) energy resolution were 10.19%, +/-0.68%, 8.36% and 13.45% FWHM, respectively. The measured coincidence time resolution between the block detector and a fast reference detector (around 200 ps single photon timing resolution) was 0.95 ns. When tested with Siemens Cardinal electronics the performance of the detector blocks remain consistent. These results demonstrate that the TSV-MPPC is a promising photon sensor for use in a flat panel PET insert composed of many high resolution compact detector modules.

Fetal heart rate baseline estimation with analysis of fetal movement signal.

In order to assign appropriate baseline estimation algorithms to different fetal heart rate tracing, a method to evaluate the fetal heart rate (FHR) baseline combining with the fetal movement information was proposed. Fetal actography and tocography were used to extract the fetal movement information. The results showed that the combined method, where the fetal movement detection result was the union of results of actography and tocography, achieved a better performance with the highest sensitivity and an acceptable positive predictive value (PPV). Furthermore, the mean absolute errors (MAEs) of basal FHR values between the two algorithms and the expert were calculated with respect to the duration coefficient of fetal movement. The results showed that the algorithm using empirical mode decomposition (EMD) and Kohonen neural network (KNN) had lower MAEs than a traditional linear baseline estimation algorithm as the duration coefficient increased. However, if the duration coefficient is below 0.2, the errors may be tolerant for the FHR baseline estimation by a linear baseline estimation algorithm, which indicates that different algorithms may be selected for FHR baseline estimation based on different duration coefficients of fetal movement.