HYPER Image developing a hybrid PET-MR

menschliche anatomie mit blutkreislaufIn recent years, advances in biomedical sciences are boosted by the introduction of new non-invasive imaging technologies. Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) or Computerized Tomography (CT), are now widely used to diagnose the development and progression of several pathologies, including cardiovascular diseases and cancer.

illustration of a whole body being illuminated by a radiant light shape around the heart region

The integration of anatomic (CT) and functional (PET) imaging is emerging as a new diagnostic tool. PET, the most sensitive molecular imaging modality, combined with CT scans provides anatomical reference for lesion localization. However, PET/CT has drawbacks and limitations: requirement of radiation, and reduced soft tissue contrast when compared to MRI. In order to overcome these shortcomings, and thanks to the recent advances in the field, MRI has the potential to be considered as alternative of CT usage, and in combination with PET, excellent human anatomical information, superior soft tissue characterization, and temporal resolution would be reached.

The HYPERImage project drives the development of a brand new system for simultaneous whole-body PET-MR imaging for humans. The goal is not only to improve the existing diagnostic applications, but also to open up new fields in therapy guidance and therapy response monitoring. Sharing knowledge and resources of a leading medical company, three academic partners and three research institutes from five EU member states HYPERImage has a well positioned partner consortium. The project work packages are divided into three major research areas: hardware development, systems analysis development, and systems pre-clinical and clinical validation.

We combine leadership in technology with pioneer experience in the use of biomedical imaging. We strongly believe that PET-MR systems will dramatically improve the way to diagnose and to treat human disease.

Treatment for Acne

The degree of acne varies for every person. Many cases of acne contain non-inflammatory whiteheads and blackheads in addition to smaller inflammatory pimples. However, some people experience much more serious blemishes, called nodules. While these blemishes is probably not as serious as acne cysts, having multiple acne nodules may become painful. Various topical treatments may lessen pain and inflammation if you suffer from acne nodules.

Identification

Acne nodules vary from smaller pimples within both size and depth. Acne nodules occur as soon as the wall of your clogged follicle bursts deep within the skin. The debris and bacteria from inside the pore then spills out into the dermis. Alternatively, the middle layer of skin. The problem then invades surrounding follicles. This technique produces a large, red bump which may be tender to touch. Unlike cysts, nodules are firm and might be felt deep inside the skin.

Benzoyl Peroxide

Benzoyl peroxide is definitely an ingredient in several over the counter acne cures. Products containing benzoyl peroxide will come such as cleansers, gels or lotions. By fighting bacteria as well as reducing excess oil production, Benzoyl peroxide helps reduce inflammatory breakouts. The most common side effect of benzoyl peroxide treatment is excessive drying of the skin, according to the American Academy of Dermatology’s AcneNet. May be effective at treating or preventing an occasional acne nodule, though benzoyl peroxide is primarily indicated for mild acne.

Topical Antimicrobials

For chronic acne nodules or multiple nodules, prescription treatment could be warranted. Topical antimicrobials focus primarily on fighting the Propionibacterium acnes bacteria. These bacteria live of the epidermis and give rise to inflammatory bad acne. Topical antimicrobials can be prescribed in addition to treatments that concentrate on factors aside from bacteria. erythromycin, azelaic and Clindamycin acid are samples of antimicrobials prescribed for acne. Possible side effects include skin irritation and dryness.

Topical Retinoids

For moderately severe cases of acne nodules, topical retinoids might be prescribed. Tretinoin, a topical retinoid, effectively treats acne partly by keeping the pores clear, according to MayoClinic.com. Topical retinoids also lighten the facial skin, which can reduce discoloration or red spots a result of cystic acne. In addition they replace old skin with new skin and reduce the sloughing of the dead skin cells, which prevents a buildup of old skin debris from clogging pores. Possible side effects include increased sun sensitivity and severe dryness, redness, stinging or peeling of our skin.

Considerations

Acne nodules really are a severe method of pimples and really should be evaluated with a dermatologist. People that have problems with mild acne could get the occasional acne nodule that could be addressed with over the counter products. Chronic breakouts of multiple acne nodules and cysts warrant dermatological care, however. Scarring migh result from delaying treatment. Sufferers must not make an effort to squeeze or pop acne nodules mainly because they occur deep within the skin. Topical treatments will not be sufficient to take care of more serious sorts of acne, which might require oral medications for successful treatment.

Technologies

1: Improved PET Detector Sensitivity

ToF- Benefit: The probability to detect the two coincident gammas of a positron annihilation scales with the solid angle of the PET scintillator array and its thickness. As this single crystal material is very expensive and the available room for a PET detector inside the MR is limited, the placement of a high sensitive whole-body PET/MR system is almost impossible. But when exploring the arrival time difference of the two gammas, more information is available per event leading to a faster conversion of the image. This is equivalent to a higher sensitivity of the system and increases the noise equivalent count rate (NEC), depending on the object size and the achievable resolving time within the Line of Response (LOR). The ToF principle and benefit is shown in Figure 1.2.1.

The left plot shows the ToF principle. The right plot shows the effective sensitivity gain, expressed by the ratio in NEC: pixelated SiPM ToF-PET readout compared to a PMT based non-ToF detector – assuming equal scintillator geometry
The left plot shows the ToF principle. The right plot shows the effective sensitivity gain, expressed by the ratio in NEC: pixelated SiPM ToF-PET readout compared to a PMT based non-ToF detector – assuming equal scintillator geometry

The count rate capability of PMT based systems is normally limited by the necessary light sharing principle, which produces signal pile-up. The NEC increases by removing the pile-up with a pixelated SiPM readout. But really dramatic improvements can be seen with the addition of the ToF benefit based on 200 ps timing resolution. The gain in sensitivity is 10 for an average patient size (27 cm diameter phantom) with an average activity (0.1 µCi/cc) used for FDG oncology studies.

In real life, this timing resolution can only be measured by having adequate scintillator, detector and electronics. As LYSO is currently the of the best scintillators for PET with high stopping power, fast decay time and very good timing characteristics, the project relies on this as a main component. Alternative scintillators like LaBr3 or LuI2 are promising, but mechanically very delicate to handle as they are hygroscopic and brittle.

Solid-State detection based on SiPMs:
The fast detection of the scintillator light is achieved by dedicated Avalanche-Photo-Diodes (APDs), so called SiPMs. Compared to APDs, which operate in the amplification mode with a gain of ≈100, SiPMs consists of parallel connected small APDs (10-50 µm), which are driven above the breakdown voltage in Geiger-Mode, see Figure 1.2.2. Each charge generating an avalanche produces very precise pulses with a constant gain of ≈106 and a very low timing jitter (<100 ps).

As the characteristics of an SiPM pixel is determined by the summing several cells, a very clean process is essential to reduce the dark-counts and increase yield. So far, no device of the desired 3-4 mm pixel is available. Also, most published SiPM designs are based on a straight forward n-on-p structure, which is not sensitive enough for the blue light of the scintillator. PDEs of <10 % are the consequence, yielding PET performance worse than PMT bases systems.
It is therefore a big challenge to establish a process with sufficient yield and develop a design with a PDE > 60 %, which is in principle possible.

The SiPM working principle showing an electrically parallel connected set of small APD cells driven in Geiger-Mode, each having an individual quench resistor, Source: FBK

Multi-Channel Readout with TDC/ADC ASIC:
The solid-state readout for SiPMs requires ~100 times the number of readout channels compared to current PMT based systems as SiPMs are 3-4 mm compared to PMTs of 30-40 mm diameter. The challenge is to design a highly integrated low power ASIC to perform time-stamping and energy estimation for each channel. An initial two channel version of this ASIC has already proven to yield CRT = 340 ps and DE/E = 13 % for a LYSO on PMT setup with an internal jitter of 105 ps [3]. A 16-channel version of this TDC/ADC is currently being investigated with an intrinsic timing jitter of 60 ps and an intrinsic energy resolution of 0.5 %, operating at 80 mW/channel (see Fig.3)

As all noise input is translated into timing and energy jitter, the layout for very low cross talk is a real challenge. All analogue (and most digital) components are based on differential designs in order to be very insensitive to electronic noise, spikes, and MR related RF induction, as well as eddy currents due to the gradient field. Also, the analogue bandwidth has to be tailored to minimally overlap with MR frequencies. Appropriate packaging of the ASIC is essential to maintain a short analogue path to the sensor, as well as achieving a small form factor needed for whole-body PET inside the MR. Very important is the reduction of the power to reduce the effort of the cooling system and allow room temperature operation, which is essential for the SiPMs to guarantee low dark counts.

The block diagram of existing multi-channel ToF-PET ASIC designed by Peter Fischer (UH) for Philips

2: Integration of Whole-body PET/MR for simultaneous imaging

Major modification to an existing MR system have to be made to house the PET detector, provide the infrastructure like power, communication and cooling. They all have to maintain the existing MR image quality, which requires a minimally disturbing PET detector.

On the other hand, the PET data acquisition has to be undisturbed by the MR, including magnetic field, gradient- and RF pulses. The minimization of the crosstalk for concurrent image acquisition is the biggest research challenge of the project and requires a profound understanding of the two complex systems. This includes a joint multi-disciplinary approach:
It starts with the selection of the correct of components, which have to be non-magnetic and also transparent to x-ray (depending on the position). Knowledge, experience and powerful simulation tools are necessary to design an effective shielding concept, which has be transparent for gradient and resonant for the RF. Noise sources have to be identified and quantified by dedicated test procedures like dedicated MR sequences or by putting the PET system in various modes.

Innovative solutions have to be found to minimize eddy currents within the PET electronics and the shielding, as it causes vibrations and lead to reduced MR image quality. Last but not least dynamic mechanical simulations help to find optimal mechanical suspension of the integrated PET system to guarantee a stable operation.

To ensure a fast and effective solution of concurrent PET/MR image acquisition, a straight forward three step approach is suggested here – and if will be explained in more details in work plan strategy in Section B1.3: First, a small test ring is investigated before a full animal PET/MR test system is realized in the second year. The third year addressed the whole-body ToF-PET/MR system for clinical tests.

3: Real-time motion correction

PET images allow an excellent quantitative view towards biochemical and physiological processes due to the outstanding pico-mol sensitivity, but they contains only minor anatomical information. It is thus beneficial to combine the functional PET image with an image modality delivering anatomical information. The commercial success of combined PET/CT systems are a good example of that. However, the advantages of the combination of PET and MR is much more than a replacement of an anatomic modality. Replacing CT by MR will allow to eliminate the CT dose exposure, while enabling real-time monitoring of organ motion as it provides truly simultaneous imaging. Nonetheless, organ motion still poses a severe problem in PET imaging in that it reduces sensitivity by blurring out small regions of radiotracer uptake and dramatically reducing their contrast.

Therefore, motion compensated reconstruction algorithms aim at the exploitation of all data to improve the sensitivity. Algorithms will be developed and validated using phantom and small animal data from an existing PET/MR system at KCL and compared to stand alone whole-body MR and PET/CT systems. Realistic human data will be obtained from a ‘GATE’-validated PET simulation using real dynamic human MR data as input. The real-time implementation of the motion-compensation into the PET reconstruction will be a challenging task and will require excellent knowledge of the data flows from both systems.

The MR also provides additional functional information, which is not available from CT: imaging of diffusion tensors, temperature, and tissue elasticity, image pH value or angiogenesis, up to metabolite concentrations by MR spectroscopic imaging. This data can conveniently be acquired while doing the PET imaging. A tool to display and analyse large 4D multi-functional data sets will be generated.

Advances the project will bring about

Whole body PET/MR with dramatically improved time-of-flight capability will enhance existing clinical and research applications, and will enable totally new ones. For many clinical studies (including gynaecological, prostate and brain tumours, soft tissue sarcoma, and paediatrics) MR is the preferred anatomical modality, due to the lack of radiation dose and excellent soft tissue contrast. Consequently, PET/MR is very likely to replace PET/CT in the future.

Simultaneous acquisition of complementary functional information from both PET and MR will increase the power of studies where interventions such as drug administration, sedation, experimental stimuli etc. are required. For example, in the heart, the simultaneous highly accurate measurements of both perfusion and wall motion in response to dobutamine could have a major clinical impact. In research applications PET/MR will allow direct translation between pre-clinical and human studies. Correction for subject motion, hand-in-hand with dramatically enhanced time-of-flight capability will greatly improve PET image quality, particularly in whole-body scanning, resulting in greater sensitivity and specificity for lesion detection and improved quantification of tracer uptake – these are key issues in the management of lung and many other cancers. The technical developments that we propose in this project constitute a major step towards the realisation of all these new applications.

Key aspects that will ensure advances are

the proposed PET/MR technology is based on next generation photodetectors that are both ideally suited for PET/MR whilst simultaneously providing dramatically enhanced time-of-flight capability
developping the novel data acquisition and processing methods necessary to ensure that we can realise the novel applications above

Literature

Suleman Surti, Joel S. Karp, Lucretiu M. Popescu, Margaret E. Daube-Witherspoon, and Matthew Werner:
Investigation of time-of-flight benefit for fully 3-D PET, IEEE TRANSACTIONS ON MEDICAL IMAGING 25 (5): 529-538
MAY 2006
Grazioso: PET Performance of PET-MR Brain Insert Tomograph, 2005 IEEE Nuclear Science Symposium Conference
Record M08-08
Peter Fischer, Ivan Peric, Michael Rizert and Torsten Solf: Multi-Channel Readout ASIC for ToF-PET I, 2006 IEEE
Nuclear Science Symposium Conference Record M11-140,